Evaluation of Speech Perception and Psychoacoustic Abilities Following Chemotherapy

Dissertation

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of

Philosophy in the Graduate School of The Ohio State University

Melissa Skarl Kappes, M.A.

Graduate Program in Speech and Hearing Science

The Ohio State University

2018

Dissertation Committee

Lawrence Feth, Ph.D. Advisor

Christina Roup, Ph.D.

Eric Bielefeld, Ph.D.

Copyrighted by

Melissa Skarl Kappes

2018

Abstract

High-frequency sensorineural hearing loss is a common side effect of platinum-

based chemotherapies and is the result of the degeneration of cochlear structures

including inner and outer hair cells, the spiral ganglion neurons and, in some extreme cases, stria vascularis. Changes in pure tone thresholds due to platinum chemotherapies have been widely documented. However, the speech perception of individuals with hearing loss due to chemotherapy has not been as extensively investigated. Studies that have investigated the speech perception abilities in individuals with hearing loss due to chemotherapy reveal speech perception difficulties and self-perceived hearing handicap greater than expected given pure tone thresholds.

This suggests that platinum-based chemotherapies reduce speech perception abilities more than expected given pure-tone thresholds and supports the need for further

evaluation of potential underlying mechanisms, such as substantial cochlear damage.

Evaluation of the cochlear function in individuals with hearing loss due to chemotherapy

may provide greater insight into poorer than expected speech perception abilities.

The purpose of the present study was to investigate both speech perception

abilities and cochlear function in children and adults with high-frequency sensorineural

ii hearing loss due to chemotherapy. Speech perception was evaluated for sentence

stimuli that were low-pass filtered to create five filter conditions and presented in the presence of speech spectrum noise at three signal-to-noise ratios (SNR). Speech stimuli were presented via hearing aids programmed using the Desired Sensation Level target gain prescription based on the participant’s pure tone thresholds. Verification of the hearing aid output revealed that participants had access to the full speech spectrum between 2000 and 8000 Hz, depending on pure tone thresholds. Cochlear function was

investigated as a mechanism to identify regions of substantial cochlear damage using

Fast Psychophysical Tuning Curves (PTCs) and the Threshold Equalizing Noise (TEN) test.

Speech perception and cochlear function were measured in four groups of participants:

30 children with normal hearing; 15 adults with normal hearing; five children with

hearing loss due to chemotherapy; and five adults with hearing loss due to

chemotherapy.

Participants with hearing impairment generally had poorer speech perception in

noise across all filter cut-off and SNR conditions and showed smaller gains in speech

perception as the filter-cut off frequency increased (i.e., additional high-frequency

audibility) when compared to normal-hearing controls. Results of the TEN test revealed

normal masked thresholds for the majority of the participants with hearing impairment.

For one child and one adult with hearing impairment, TEN test results demonstrated abnormally high masked thresholds, meeting the criteria for substantial cochlear

iii damage. These two participants with hearing impairment also had smaller gains in speech perception as low-pass filter cut-off frequency increased when compared to other participants with hearing impairment. Thus, the TEN test was able to identify participants with hearing impairment who had notably poorer speech perception in all

SNR conditions and who had smaller gains in speech perception as low-pass filter cut-off frequency increased when compared to other participants with hearing impairment.

Fast PTCs were successful in identification of normal cochlear function in regions of normal hearing for the participants with hearing impairment. In contrast, participants with hearing impairment were unable to complete the task when high frequencies were evaluated, regardless of the degree of hearing loss.

For some participants with hearing loss due to chemotherapy, speech perception in noise was notably poorer (greater than two standard deviations below normal) than expected, given the degree of pure tone loss. This suggests that the speech perception performance in participants with hearing loss due to chemotherapy is impacted by factors beyond what the pure tone threshold audiogram provides. The results of this study support the need for assessment of speech perception abilities in noise in individuals with hearing loss due to chemotherapy. In addition, further evaluation of both speech perception abilities and cochlear function, particularly using the TEN test, may help strengthen the relationship between the two measures, helping to identify individuals with substantial cochlear damage and speech perception difficulties.

iv Dedication

For Rowan and Brenna:

Without you, this journey might have been a decade shorter,

but life less meaningful.

v Acknowledgments

I owe an incredible debt to my advisor, Larry Feth. His willingness and flexibility when I brought hearing aids and children into the Psychoacoustics Lab have shown me that the results of an unlikely collaboration can be incredible. His patience and unwavering support when I needed to step back and again when I was ready to return are the only reason I was able to continue my doctoral program. A special thank you to

Christina Roup for always being my sounding board and sometimes being my drill sergeant. I knew I would walk out of her office better than when I walked in. And to

Gail Whitelaw, a heartfelt thank you for introducing me to the profession that would feed my heart and soul.

I would like to send my love and appreciation to all the fellow students who have supported me over the last 16 years; I am blessed to be part of the tribe. To Gina,

William and Jenn, my “been there, done that” club, thank you for always letting me know that I wasn’t alone and for showing me that life after Ph.D. does exist.

Thank you to all the participants and their families who participated in my study.

I am forever humbled by the patients I work with daily. I would like to acknowledge the

Ohio State University Alumni Grant for Graduate Research and Scholarship for providing

vi the necessary financial support to complete this project and Oticon Inc. for providing

loan of hearing aids.

Heartfelt thanks go to my parents for their lifetime of support, especially their

encouragement of higher education. To David, who had no idea what he was signing up

for when this journey began, thank you for not giving up on me.

And finally, a prayer of thanks to the late Mike Wynne who asked me the simple question, “Have you thought about a Ph.D.?”

vii Vita

1997………………………………………………. B.A. Speech and Hearing Science, The Ohio State

University

1999………………………………………………. M.A. Audiology, The Ohio State University

2009 - Present…………………………………Audiologist, Nationwide Children’s Hospital

Fields of Study

Major Field: Speech and Hearing Science

viii Table of Contents

Abstract ...... ii

Dedication ...... v

Acknowledgments...... vi

Vita ...... viii

Table of Contents ...... ix

List of Tables ...... xiv

List of Figures ...... xvi

Chapter 1: Introduction ...... 1

1.1: Chemotherapy and Speech Perception ...... 1

1.2: Speech Perception and Cochlear Function ...... 4

1.3: Research Objectives ...... 7

Chapter 2: Review of Literature ...... 8

2.1: Cochlear Damage due to Chemotherapy ...... 8

2.2: Chemotherapy and Speech Perception ...... 10

2.3: Speech Perception in Adults with High-Frequency Hearing loss ...... 12

ix 2.4 Speech Perception in Children with High-Frequency Hearing Loss ...... 16

2.5: Speech Perception and Cochlear Damage in Adults...... 18

2.6: Speech Perception and Cochlear Damage in Children ...... 23

2.7: Assessment of Cochlear Function ...... 24

2.8: Measures of Cochlear Function ...... 26

2.8.1: Threshold Equalizing Noise Test ...... 26

2.8.2: Fast Psychophysical Tuning Curves ...... 28

2.8.3: Fast PTCs and TEN Test Comparison ...... 31

Chapter 3: Methods ...... 35

3.1: Participants ...... 35

3.2: Participant Recruitment and Scheduling ...... 40

3.3: Materials and Procedures ...... 41

3.3.1: Pure Tone Thresholds ...... 41

3.3.1.1: Pure Tone Stimuli ...... 41

3.3.1.2: Pure Tone Threshold Procedure ...... 41

3.3.2: Word Recognition ...... 42

3.3.2.1: Word Recognition Stimuli ...... 42

x 3.3.2.2: Word Recognition Procedure ...... 42

3.3.3: Threshold Equalizing Noise Test ...... 43

3.3.3.1: TEN Test Stimuli ...... 43

3.3.3.2: TEN Test Procedure ...... 43

3.3.4: Fast Psychophysical Tuning Curves ...... 44

3.3.4.1: Fast PTC Stimuli ...... 44

3.3.4.2: Fast PTC Procedure ...... 45

3.3.5: Speech Perception ...... 49

3.3.5.1: Speech Perception Stimuli ...... 49

3.3.5.2: Speech Perception Verification of Audibility ...... 50

Chapter 4: Results ...... 53

4.1: Participants with Normal Hearing ...... 53

4.1.1: Speech Perception in Adults and Children ...... 53

4.1.2: Threshold Equalizing Noise Test ...... 60

4.1.3: Psychophysical Tuning Curves in Adults with Normal Hearing ...... 63

4.1.4: Psychophysical Tuning Curves in Children with Normal Hearing ...... 69

4.2: Participants with Hearing Impairment ...... 77

xi 4.2.1: Speech Perception ...... 77

4.2.2: Threshold Equalizing Noise Test ...... 83

4.2.3: Psychophysical Tuning Curves ...... 87

Chapter 5: Discussion ...... 93

5.1: Speech Perception ...... 93

5.2: Assessment of Cochlear Function ...... 98

5.3: Special Cases in Participants with Hearing Impairment ...... 104

5.3.1: Hearing-Impaired Adult Participant #1 ...... 105

5.3.2: Hearing-Impaired Adult Participant #4 ...... 107

5.3.3: Hearing-Impaired Adult Participant #5 ...... 112

5.3.4: Hearing-Impaired Child Participant #1 ...... 114

5.4: Study Limitations, Future Research and Clinical Feasibility ...... 116

Chapter 6: Final Conclusions ...... 119

Bibliography ...... 122

Appendix A: Curve-fitting procedures for the Fast-PTC software ...... 132

Appendix B: Examples of Audibility Verification ...... 138

xii Appendix C: Adult and child average TEN thresholds with standard deviation for each frequency and intensity level ...... 142

Appendix D: Fast PTC Rejection Criteria ...... 143

Appendix E: Verification of Audibility and Speech Perception Performance for Hearing-

Impaired Participants ...... 146

xiii List of Tables

Table 1: Sex, age, ear tested, type of cancer, and type of intervention for individual participants with hearing impairment...... 37

Table 2: Success rate of each tip estimate method by frequency in adults...... 65

Table 3: Success rate of each tip estimate method by frequency in adults...... 66

Table 4: Number of PTC pairs, average error difference and standard deviation between

PTC pairs for each tip-frequency estimation method at each frequency in adults...... 68

Table 5: Total number of PTCs attempted at each frequency and the overall success rate

in children...... 70

Table 6: Success rate of each tip estimate method by frequency in children...... 71

Table 7: Mean, standard deviation, and minimum tip frequency error for each method at each frequency in children...... 73

Table 8: Number of PTC pairs, average error difference and standard deviation between

PTC pairs for each tip frequency estimation method at each frequency in children...... 76

xiv Table 9: Ear(s) tested and full and partial audibility cut-off frequencies for participants with hearing impairment...... 78

Table 10: Acceptable tuning curves and method success rate for adult and children with hearing impairment...... 89

Table 11: Mean, standard deviation, and minimum tip frequency error for each method is presented by frequency for participants with hearing impairment...... 92

List of Figures

Figure 1: Pure tone thresholds are provided for the adults with hearing impairment. The grey shaded area represents normal hearing. Red symbols indicate right ear and blue symbols indicate left ear ...... 38

Figure 2: Pure tone thresholds are provided for the children with hearing impairment.

The grey shaded area represents normal hearing. Red symbols indicate right ear and blue symbols indicate left ear...... 39

Figure 3: Raw data for a 2000 Hz PTC presented at 30 dB SPL for the left ear of normal- hearing adult participant 11. The green dot indicates the probe intensity level and frequency...... 48

Figure 4: Average words correctly identified per condition as a percent correct speech score (± 1 SD) at each SNR and frequency condition for adults with normal hearing using the MLST...... 56

Figure 5: Average words correctly identified per condition as a percent correct speech score (± 1 SD) at each SNR and frequency condition for children with normal hearing using the MLST...... 56

xvi

Figure 6: Average words correctly identified per condition as a percent correct (± 1 SD) at each SNR and frequency condition for adults (black) and children (color) with normal hearing using the MLST...... 57

Figure 7: Average normal-hearing adult masked threshold (+2 SD) for 30, 50 and 70 dB

HL TEN presentation levels at 500, 1000, 2000 and 4000 Hz...... 61

Figure 8: Average normal-hearing child masked threshold (+2 SD) for 30, 50 and 70 dB

HL TEN presentation levels at 500, 1000, 2000 and 4000 Hz...... 61

Figure 9: Hearing-Impaired adult participant speech perception data as compared to the average (± 1 standard deviation) normal-hearing adult participant data. From left: -3 dB

SNR, 0 SNR, +3 SNR...... 81

Figure 10: Hearing-Impaired child participant speech perception data as compared to

the average (± 1 standard deviation) normal-hearing child participant data. From left: -3

SNR, 0 SNR, +3 SNR...... 82

Figure 11: Individual masked thresholds for the adults with hearing impairment using

the TEN test with average adult mean (+2 SD). An asterisk (*) indicates abnormally high

masked threshold...... 85

xvii

Figure 12: Individual masked thresholds for the children with hearing impairment using the TEN test with average child mean (+2 SD). An asterisk (*) indicates abnormally high masked threshold...... 86

Figure 13: Fast PTC raw data results for a 1500 Hz probe tone for the right ear of

Hearing-Impaired Adult Participant #4 ...... 111

Figure 14: Fast PTC raw data results for a 4000 Hz probe tone for the right ear of

Hearing-Impaired Adult Participant #4 ...... 111

Figure 15: Double Linear Regression analysis for a 2000 Hz PTC...... 133

Figure 16: Two and Four Point Moving Average analysis for a 2000 Hz PTC...... 134

Figure 17: Quadratic Function analysis for a 2000 Hz PTC...... 135

Figure 18: Three variation of the Double Low-Pass Filtering analysis for a 2000 Hz PTC.

...... 136

Figure 19: RoEx analysis for a 2000 Hz PTC...... 137

Figure 20: Screenshot of graphic and tabular results of Verifit 2 Speechmapping for

normal-hearing control participants...... 140

xviii

Figure 21: Screenshot of graphic and tabular results of Verifit 2 Speechmapping for hearing-impaired child participant #5 with audibility cut-off frequencies noted...... 141

Figure 22: Screenshot of raw data for a 2000 Hz PTC with abnormally flat region near tip

frequency...... 143

Figure 23: Screenshot of raw data for a 2000 Hz PTC with abnormal “w” shape...... 144

Figure 24: Screenshot of raw data for a 4000 Hz PTC with abnormally long level

difference (here greater than 50 dB)...... 145

xix

Chapter 1: Introduction

1.1: Chemotherapy and Speech Perception

Platinum chemotherapies, such as cisplatin and carboplatin, are used in the treatment of a wide range of tumor-based cancers including bone, brain and nerve tissues, eyes, liver, breast and lung. Despite their effectiveness in treating many cancers, one notable side effect of platinum chemotherapies is high-frequency

sensorineural hearing loss (Knight et al., 2005). High-frequency sensorineural hearing

loss due to chemotherapy exposure has been extensively documented (Brock et al.,

2012; Chang, 2011; Knight et al., 2007; Landier et al., 2014). There are far fewer

published papers evaluating speech perception abilities following chemotherapy

(Einarsson et al., 2010, 2011a, 2011b). Results of those speech perception studies found

that participants with hearing loss due to chemotherapy had significantly poorer speech

perception abilities and significantly greater self-perceived hearing handicap than pure

tone thresholds would suggest. In addition, no published research has specifically

addressed the speech perception abilities of children with hearing loss due to

chemotherapy. Speech perception directly impacts communication abilities and poor

speech perception can negatively influence quality of life (Pichora-Fuller & Singh, 2006).

The negative impact of poor speech perception can be especially harmful in cancer

survivors who may also have confounding issues including neurocognitive damage as

well as the social and emotional effects of the cancer and chemotherapy (Gurney et al.,

2007). Further investigation regarding the relationship between speech perception

deficits and potential underlying mechanisms in both children and adults with hearing

loss due to chemotherapy is warranted.

A cornerstone in the investigation of speech perception research is the provision

of amplified sound so that the speech signal is intense enough for the participant with

hearing impairment to perceive the sound (Ching et al., 1998; Ching et al., 2001;

McCreery & Stelmachowicz, 2011; Scollie et al., 2005). A participant would not be

expected to have improved speech perception without first having access to the speech

signal. Access to the speech signal is termed audibility. Audibility can be provided in

various ways including speech signal amplification on a computer presented to the

participant via headphones or sound field speakers. Alternatively, it can be provided at

ear level through a hearing aid.

Speech perception in individuals with high-frequency sensorineural hearing loss without exposure to chemotherapy has been extensively studied (Amos & Humes, 2001;

Ching et al., 1998; Hornsby & Ricketts, 2006; Stelmachowicz et al., 2004). Adults with a

mild-to-moderate high-frequency sensorineural hearing loss typically have improved

speech perception performance as high-frequency speech spectrum audibility increases

(Ching et al., 1998; Ching et al., 2001). However, for participants with greater than a moderate degree of high-frequency sensorineural hearing loss (as is often seen in hearing loss due to chemotherapy), speech perception performance varies between participants. As the degree of high-frequency hearing loss worsened, smaller improvements in speech perception performance were made as access to the high- frequency speech spectrum audibility increased (Ching et al., 1998; Hogan & Turner,

1998, Hornsby & Ricketts, 2006). These studies suggest that participants with greater than a moderate degree of high-frequency hearing loss were less able to utilize the additional audibility for improvements in speech perception performance as compared to participants with a mild to moderate degree of high-frequency hearing impairment.

A notable group of studies have identified a small subset of participants with high-frequency hearing impairment ranging from moderate to severe who failed to demonstrate improved speech perception when high-frequency audibility was provided through signal processing in both adult (Amos & Humes, 2001,2007; Ching et al., 1998;

Sullivan et al., 1992; Turner & Cummings, 1999) and pediatric populations (Malicka et al., 2008; Malicka et al., 2010; Moore et al., 2003; Munro et al., 2005). More importantly, some studies have found decreases in speech perception performance when high-frequency audibility has been provided for adults in quiet conditions (Hogan

& Turner, 1998; Vickers et al., 2001) and noise conditions (Baer et al., 2002). Thus, pure-

tone thresholds do not appear to be an effective means of identifying individuals who would or would not have improved speech perception from high-frequency amplification.

1.2: Speech Perception and Cochlear Function

Assessment of an individual’s cochlear function may offer information about speech perception abilities not provided by the audiogram. There is a clear correlation between grossly abnormal cochlear function and reduced speech perception abilities in adults (Baer et al., 2002; Van Tasell, 1993; Vickers et al., 2001). Results from studies of children with high-frequency hearing loss suggest that when measures indicated grossly abnormal cochlear function, children also had severe speech perception difficulties

(Malicka et al., 2009, 2010; Munro et al., 2005). Thus, beyond evaluation of cochlear damage, better understanding of a listener’s cochlear function may also provide insight into speech perception abilities. However, research evaluating both cochlear function and speech perception has not yet included participants with hearing loss due to chemotherapy. Evaluation of both cochlear function and speech perception of individuals with hearing loss due to chemotherapy would provide additional information on the underlying mechanisms contributing to poorer speech perception.

Research suggests that poor speech perception in participants who do not

benefit from high-frequency audibility is due to cochlear damage so great that the inner hair cells and/or their spiral ganglion neurons are non-functional and no information can

be transmitted in that region of the cochlea (Moore et al., 2000; Moore, 2004; Vickers et

al., 2001). Moore et al. (2000) called non-functioning inner hair cells and/or neurons a

“cochlear dead region”. Acoustic information falling within this damaged region can

only be transmitted via energy spread into nearby cochlear regions with functional

structures. Given that platinum chemotherapies can cause regions of hair cell death and

degeneration of spiral ganglion neurons (Hofstetter et al., 1997; Laurell & Bagger-

Sjoback, 1991), it is likely that some individuals with hearing loss due to chemotherapy

will have cochlear dead regions and be at high risk for significant speech perception

difficulties.

To evaluate cochlear function (specifically identification of cochlear dead

regions) in a clinical setting, Moore et al. (2000) devised a proprietary masking paradigm using a Threshold Equalizing Noise (TEN) masker. When presented to participants, TEN masking noise will elevate pure tone thresholds. In frequency regions where cochlear damage impairs sensory transduction of the acoustic signal, masked thresholds will be more than 10 dB higher than the level of the TEN noise. High masked thresholds are judged as indication of substantial cochlear damage in that frequency region (Moore et

al., 2000).

Psychophysical tuning curves (PTCs) have been used for many years as a

laboratory measure of frequency selectivity (Chistovich, 1957; Small, 1959). In PTC

measures, a probe tone is presented at a low level, and the level of a simultaneous

masker (tone or narrow band noise) required to just mask the probe tone is measured

as a function of the masker frequency. Laboratory PTC procedures require one to three

hours of training, limiting the clinical application of PTCs in populations including

children and older adults. A “Fast PTC procedure” was devised to address concerns with

the feasibility of obtaining PTCs in special populations and was designed to be utilized in a typical audiology clinic (Sęk et al., 2005; Sęk & Moore, 2011; Sęk et al., 2007).

Research on Fast PTCs have included children and adults in laboratory settings; however

Fast PTCs have only been measured recently in a clinical setting with adults (Pepler et al., 2014). As such, an investigation into the feasibility of using Fast PTC procedures, particularly in children with hearing impairment, is warranted.

Both Fast PTCs and the TEN test have been proposed as clinical methods for evaluation of cochlear function and the identification of substantial cochlear damage in individuals with hearing loss, particularly high-frequency hearing loss. It has recently

been hypothesized that agreement between the two tests may be dependent on the

type of cochlear damage (Warnaar & Dreschler, 2012). However, no research has been

published controlling for the etiology of the hearing loss. Evaluation of the TEN and Fast

PTC tests in participants with hearing loss due to chemotherapy is an important step in assessing the impact of cochlear function on speech perception in this population.

1.3: Research Objectives

The primary purpose of this study is to evaluate the speech perception abilities

and cochlear function as indicated by results from the TEN and Fast PTCs test in the

same participants. By selecting participants with hearing loss due to chemotherapy, a

connection between speech perception, psychoacoustic measures, and presumed

cochlear damage can be made while limiting the variability due to the mechanism of

damage associated with the TEN and Fast PTC tests.

Chapter 2: Review of Literature

2.1: Cochlear Damage due to Chemotherapy

Platinum chemotherapies, such as cisplatin and carboplatin, are used in the treatment of a wide range of cancers. Cisplatin and carboplatin are effective in treating many cancers, however, one notable side effect is ototoxicity (Knight et al., 2005).

Ototoxicity occurs when administration of the drug causes damage to the inner ear.

Ototoxicity due to chemotherapy most commonly causes cochlear hair cell damage, resulting in sensorineural hearing loss. Research suggests that between 11% and 90% of children and adults receiving chemotherapy will exhibit bilateral, permanent sensorineural hearing loss (Bertolini et al., 2004; Knight et al., 2005; Landier et al., 2014;

Zuur et al., 2007).

Current platinum-based chemotherapy monitoring protocols typically include pure tone testing and or measurement of otoacoustic emissions (Durrant et al., 2009).

The pure tone threshold elevation due to chemotherapy exposure has been extensively documented (Bergeron et al., 2005; Gurney & Bass, 2012; Knight et al., 2005; Orgel et al., 2015). Sensorineural hearing loss due to chemotherapy typically begins in the ultra-

high frequencies (above 10,000 Hz) and, with increasing exposure and dosage, progresses into lower frequencies, eventually affecting the speech frequency range

(below 8000 Hz). A number of individuals with hearing loss due to chemotherapy will experience progression of their hearing loss, even as long as five years following the last treatment (Berg et al., 1999; Knight et al., 2007; Stöhr et al., 2005).

The cochlea is particularly sensitive to the effects of platinum drugs. The primary anti-neoplastic or tumor reduction response of platinum chemotherapies is to enter the tumor cells and as the drug is broken down, platinum derivatives bond with cell DNA, effectively altering cell division. Further, reactive oxygen species (ROS) production increases, causing oxidative stress and activating apoptosis (active cell death) pathways

(Helt-Cameron & Allen, 2009). Brock et al. (2012) describe a blood-labyrinth barrier within which the hair cells reside. Platinum drugs can cross this barrier and bind with the cellular DNA. In addition, the cochlea is unable to quickly flush out the platinum derivatives, leading to a concentration of those derivatives and, later, ROS. The ROS are often present in the cochlea long after other systems in the body are clear, causing further cell structure damage and subsequent cell apoptosis (Rybak et al., 2009).

Cochlear damage due to platinum drugs includes initial degeneration of outer hair cells with progression to inner hair cells in a base-to-apex pattern with increasing dosage/exposure (Hinojosa et al., 1995; Hofstetter et al., 1997; Laurell & Bagger-

Sjoback, 1991). The outer hair cells at the base of the cochlea are affected first, starting

with loss in the ultra-high frequencies (above 8000 Hz) progressing into the speech frequency range. With greater exposure (e.g., dosage and duration), more of the speech frequency range is affected, both with greater severity of high-frequency loss

and additional frequencies being compromised (Hinojosa et al., 1995). In addition to

the base-to-apex progression with increasing dosage, there is also a lateral progression with hair cell damage progressing from the outermost row of outer hair cells to the inner two rows of outer hair cells and finally to the inner hair cells. Additional cochlear structures are affected with higher levels of exposure, including the spiral ganglion neurons, spiral ligament and stria vascularis (Klis et al., 2000; Ravi et al., 1995; Tsukasaki

et al., 2000; Van Ruijven et al., 2005).

2.2: Chemotherapy and Speech Perception

There are few published papers evaluating speech perception abilities following

chemotherapy. A study of young adults with hearing loss due to chemotherapy found

that in addition to a progressive hearing loss (particularly above 2000 Hz), participants

reported greater hearing handicap and disability due to the hearing loss than would be

expected given pure tone thresholds, particularly in noisy environments (Einarsson et

al., 2010). A 2011 follow-up study by Einarsson et al. found that young adults with hearing loss due to chemotherapy had speech perception performance in noise that was

notably poorer than hearing thresholds alone would predict and was poorer in

comparison to participants with similar hearing losses not due to chemotherapy

(Einarsson et al., 2011a). Einarsson et al. (2011b) found that unaided word recognition

in noise for young adults with hearing loss due to chemotherapy was significantly poorer

than would be expected given pure tone thresholds alone. Given that the Einarsson et

al. studies focused on a small number of young adults, evaluation of speech perception

performance in children and older adults with hearing loss due to chemotherapy is

warranted.

In addition to pure tone threshold elevation, children may also experience

additional side effects of chemotherapy that can negatively affect speech perception.

Children who have received chemotherapy are at risk for learning delays,

developmental delays, communication delays, social interaction delays, poor school

performance and overall reduced quality of life (Gurney et al., 2007; Gurney et al., 2009;

Skinner, 2012). A recent study investigating the effects of hearing loss on the

neurocognitive function of children with brain tumors found that children with hearing

loss due to chemotherapy were at a higher risk for neurocognitive deficits as compared

to children with brain tumors but no hearing loss (Orgel et al., 2016). Neurocognitive

deficits due to chemotherapy include poorer auditory working memory, poorer abstract

verbal reasoning and delayed processing speed, all of which impact speech perception abilities, particularly in noise (Orgel et al., 2016). It follows that young children with

hearing loss due to chemotherapy would be further affected due to the additional neurological effects of chemotherapy, causing children with hearing loss due to chemotherapy to be notably delayed in auditory development. A better understanding of how children with hearing loss due to chemotherapy use audible information for speech perception, both in quiet and in noise, is critical in long term management, including development of auditory-based intervention strategies.

2.3: Speech Perception in Adults with High-Frequency Hearing loss

Few published studies evaluate speech perception in participants with high- frequency hearing loss due to chemotherapy. In contrast, there is a large body of research investigating speech perception in participants with high-frequency hearing loss of unknown or various other etiologies. Evaluation of speech perception abilities in a population with high-frequency hearing loss not attributed to chemotherapy may be helpful in providing a foundation for looking specifically at the speech perception of individuals with hearing loss due to chemotherapy.

To discuss the speech perception of individuals with hearing impairment, it is important to discuss the audibility of the speech signal first. Amplification is routinely used to address the loss of sensitivity caused by hearing loss (ototoxic and otherwise) by providing audibility of speech. Audible speech is achieved when the intensity of the

acoustic signal has been increased above the listener’s threshold and can be detected by

the listener. Audibility can be provided through different means of amplification but is

often provided using hearing aids. A fundamental principal in the provision of

amplification is prescribing audibility based on the pure tone threshold at each

frequency in order to provide an individual with hearing impairment access to speech with the best representation of the speech spectrum as can be achieved given the degree of hearing loss (Byrne et al., 2001; Scollie et al., 2005).

Ching et al. (1998) was one of the first to identify listeners who did not benefit

from provision of high-frequency access. In those participants with a sloping, severe,

high-frequency sensorineural hearing loss (thresholds at 4000 Hz of 80 dB HL or

greater), speech perception did not improve and in some cases was significantly poorer

when additional high-frequency information was provided. Hogan and Turner (1998)

also found that in participants with severe to profound high-frequency hearing loss,

increasing high-frequency access in quiet environments resulted in poorer perception.

A study by Sullivan et al. (1992) evaluated both speech understanding and speech quality ratings in participants with severe loss (70 dB HL+) at 2000 Hz and above. In this

study, participant’s speech perception scores improved with additional high-frequency

information in both quiet and background noise. However, participants rated speech

quality as being very poor.

Further analysis of the Hogan and Turner (1998) study revealed that participants

with a moderate, to moderate-severe high-frequency loss (greater than 55 dB HL at

4000 Hz and above) showed smaller degrees of improvement with increasing high- frequency access. Thus, with greater degrees of hearing loss, listeners made smaller gains in speech perception as high-frequency audibility increased (especially between

4000 and 8000 Hz). Turner and Cummings (1999) investigated high-frequency audibility

in quiet and found that in participants with high-frequency hearing loss, providing high-

frequency access above 3000 Hz resulted in showed little to no improvement in speech perception when hearing loss was above 55 dB HL. The results of these studies led

Turner and Cummings to recommend that when high-frequency hearing loss exceeds 55

dB HL, high-frequency access should be sparingly provided. A later set of studies by

Amos and Humes (2001, 2007) supported this recommendation, as participants with

high-frequency hearing loss had no significant improvement in word perception in noise

with the addition of high-frequency audibility above 3200 Hz.

In contrast to studies suggesting little improvement with additional high-

frequency access, Horwitz et al. (2008) measured speech perception in quiet and noise

and found that participants performed best in a broadband condition when the

frequency response of the signal was shaped specifically to their hearing loss. This was

particularly evident when speech perception was measured in noise. Hornsby and

Ricketts (2003, 2006) found that participants with sloping hearing loss had improved

speech perception performance with increasing high-frequency access. In agreement

with other studies, authors noted while improvements in speech perception were

observed, participants had smaller gains in speech perception as the degree of hearing

loss became worse.

The majority of research investigating hearing-impaired participants with up to a moderately-severe high-frequency loss suggested that increasing high-frequency access resulted in improvements in speech understanding (Hogan & Turner 1998; Hornsby &

Ricketts, 2003, 2006; Horwitz et al., 2008). However, as the degree of hearing loss became worse, participants had smaller improvements in speech understanding. This suggested that participants were less able to utilize the additional high-frequency speech spectrum energy for improved understanding (Ching et al., 1998; Hornsby &

Ricketts 2006; Hogan & Turner 1998; Turner & Cummings 1999). Researchers have termed this additional distortion a “desensitization factor” (Pavlovic et al., 1986). The desensitization factor is dependent on both level and frequency and addresses the issue that participants with hearing loss are not always able to make full use of high- frequency amplification for speech understanding. As an example, when participants have low-frequency hearing loss in the mild to moderate range they can utilize an audible signal as well as a normal hearing listener. Researchers propose that this occurs when the sensorineural hearing loss is greater than 60 dB HL due to inner hair cell damage resulting in reduced and/or distorted transmission of speech stimuli, including a

loss of frequency selectivity (Moore, 2001; Van Tasell, 1993). The loss of frequency

selectivity impedes neural coding and transmission of audible high-frequency speech

information (Moore et al., 1995); this causes distortion such that for some listeners,

even when speech is audible it may sound unnatural (Ching et al., 2000). In an extreme case, when high-frequency pure tone thresholds reach 80 dB HL, listeners could only extract a small amount of audible signal for speech perception.

2.4 Speech Perception in Children with High-Frequency Hearing Loss

Research in children with high-frequency sensorineural hearing loss suggests that children with hearing-impairment perform more poorly on speech perception tasks as compared to children with normal hearing when similar levels of audibility are provided. This suggests an inability to use audible high-frequency information as

effectively as children with normal hearing (Scollie, 2008). This is a critical issue in

speech acquisition because speech sounds not heard consistently, or not heard at all,

are unlikely to be produced appropriately, resulting in delayed speech and language skills (Moeller et al., 2007; Pittman, 2008).

The development of expressive and receptive speech skills in children with normal hearing requires acoustic information (primarily high frequency) that is not required for communication in adults with developed language skills (Stelmachowicz,

2000; Kortekaas & Stelmachowicz, 2005). Normal-hearing infants and young children

require access to the full bandwidth of speech (up to 10,000 Hz for female speakers) in

addition to slight increases in gain for low levels sounds to develop normal speech skills

(Kuk & Marcoux, 2002; Stelmachowicz et al., 2002). A recent 2015 study by Silberer and

colleagues found that when listening in quiet, school age children and adults with

normal hearing required similar speech stimuli bandwidths for maximum speech

understanding of sentences, however when listening in noise, children required

audibility beyond 8,000 Hz for maximum understanding. Given that hearing aids have

only recently been able to provide amplification beyond 6,000 Hz, children with high

frequency hearing loss are at a disadvantage when listening in background noise- even

when appropriately aided.

Infants and young children with normal hearing show a greater effect of

background noise as compared to adolescents and adults with normal hearing, requiring

better a signal-to-noise ratio (SNR) (and therefore greater signal audibility) to achieve similar levels of performance on speech discrimination and recognition tasks (Hall et al.,

2002; Litovsky, 2005; McCreery & Stelmachowicz, 2011; Nozza et al., 1990). The effect

of background noise is more pronounced in children with hearing loss, because they

require a better SNR than children with normal hearing to perform similarly on speech

recognition tasks in noise, multi-talker babble and single speaker competing signals

(Gravel et al., 1999; Sininger et al., 2010; Leibold et al., 2013). A 2012 study by Hall et

al. evaluating masking patterns in adults and children with normal hearing and with

hearing impairment found that hearing-impaired children performed the most poorly

and exhibited the slowest course of development of all groups, which the authors

suggested was support for the cumulative effects of both limited acoustic exposure due

to hearing impairment and delayed auditory pathway development.

Based on research in children with hearing loss of various etiologies, children

with hearing loss due to chemotherapy are likely to have substantial speech perception

difficulties, especially in background noise. In addition, children who have received

platinum chemotherapies (both with and without hearing loss) exhibit neurocognitive

delays including reduced attention and poorer verbal memory and processing (Gurney et al., 2007; Schreiber et al., 2014). In children with hearing loss due to chemotherapy, these neurocognitive delays would be expected to negatively affect speech perception

in an already impaired auditory system. Thus, speech perception research focused on

children with hearing loss due to chemotherapy is critical in determining the specific

needs of this population.

2.5: Speech Perception and Cochlear Damage in Adults

As was noted previously, research suggests that smaller improvements in speech

perception are seen as the degree of high-frequency hearing loss worsens (Hogan &

Turner, 1998; Hornsby & Ricketts, 2006). In addition, research in both adults and

children with high-frequency hearing loss suggests that a subset of these individuals

show significantly less benefit from high-frequency access as compared to others with

similar hearing loss (Baer et al., 2002; Malicka et al., 2008; Vickers et al., 2001).

Differences in underlying cochlear function and cochlear damage have been suggested

as the reason why some individuals show less benefit from high-frequency access

(Moore et al., 2000). Moore et al. (2000) describe the most extreme cases when the

inner hair cells and/or their spiral ganglion neurons are damaged such that no acoustic

information can be transduced in that region of the cochlea. Acoustic information

falling within this damaged region can only be transduced when the cochlear excitation

due to the acoustic energy spreads into close cochlear regions with functional

structures. A region of non-functioning inner hair cells and/or neurons have been termed a “cochlear dead region” (Moore et al., 2000).

Much research has focused on high-frequency cochlear dead regions (Cox et al.,

2012; Gordo & Iório, 2007; Moore, 2004; Munro & Malicka, 2007). Depending on the extent and configuration of a cochlear dead region, the resulting pure tone audiogram can range from a moderate to a severe sensorineural hearing loss in the frequencies corresponding to the cochlear dead region. When high-frequency audibility is provided via high intensity amplification, the acoustic information cannot be transduced within the cochlear dead region. However, the high-intensity amplification can result in a

spread of cochlear excitation into neighboring lower frequency regions where cochlear

function is less damaged. This can cause both a frequency-to-place mismatch on the

cochlea and transduction of competing speech information within a given frequency

range (Moore & Alcántara, 2001; Summers et al., 2003). In either case, the speech

signal is negatively impacted, reducing speech perception and potentially causing

distortion such that even when speech is audible it may sound unnatural (Ching et al.,

2001; Moore, 2001).

Vickers et al. (2001) and Baer et al. (2002) suggested reducing high-frequency

amplification due to the decrease in speech perception performance seen in

participants with cochlear dead regions. Mackersie et al. (2004) studied amplification

under both quiet and noise conditions in a laboratory setting for participants with

extensive dead regions beginning between 2000 and 3000 Hz. Results of the study

suggested that providing target gain more than one octave above the edge frequency of

a cochlear dead region resulted in either no improvement or decreases in speech

perception scores in high noise conditions. Gordo and Iorio (2007) evaluated speech

perception both in quiet and noise utilizing a behind-the-ear hearing aid in participants

with dead regions beginning between 1000 and 1500 Hz. Participants performed

significantly better in both quiet and noise conditions and reported better sound quality

when the hearing aid was programmed to provide no amplification above the cochlear dead region edge frequency.

One consideration in the evaluation of cochlear function is the extent of cochlear

damage. The previous studies suggesting that participants performed more poorly with

increasing high-frequency access typically included participants with wide cochlear dead regions and extensive abnormal cochlear function. When studies included participants with restricted or isolated cochlear dead regions, they did not show the same pattern of decreased speech perception performance. Preminger et al. (2005) evaluated aided speech perception in noise and found that although participants with cochlear dead regions above 2000 Hz did not perform as well as hearing-loss matched participants without dead regions, they did not perform significantly poorer. In addition, participants with cochlear dead regions reported more perceived difficulty in reverberant and high noise environments. A study by Cox et al. (2012) is unique in that participants were able to utilize amplification outside of the laboratory setting.

Participants completed speech perception testing in the lab and later wore the hearing aids in their everyday environments. Participants with isolated cochlear dead regions did not show the same levels of improvement speech perception in noise as compared to participants with similar pure tone thresholds but no cochlear dead regions. In contrast, participants with larger regions of cochlear dead regions performed more poorly with as additional high-frequency access was provided in laboratory testing.

Interestingly, even when participants had decreases in speech perception performance

in the lab, they reported a preference for and a benefit with full high-frequency access in real world settings.

Mackersie et al. (2004), Preminger et al. (2005) and Cox et al. (2012), provide no support to recommend an immediate reduction in high-frequency gain for patients with

1 to 2 dead region bands. However, participants with wide cochlear dead regions may benefit from a reduction of high-frequency access (Vickers et al. 2001, Gordo & Iorio,

2007, Baer et al., 2002). For these patients, a reduction in gain is unlikely to improve understanding, but may improve personal listening effort by reducing feedback, distortion and loudness (Moore et al., 2001).

The presence of substantial cochlear damage, or cochlear dead regions, has been suggested as an explanation why some individuals with high-frequency hearing loss are less able to use high-frequency audibility for speech perception (Moore, 2001). The pattern of cochlear degeneration due to chemotherapy has been widely investigated and supports the likelihood of substantial cochlear damage in this population

(Hofstetter et al., 1997; Laurell & Bagger-Sjoback, 1991). Given that platinum chemotherapies can cause hair cell death and degeneration of the spiral ganglion neurons, it is likely that some individuals with hearing loss due to chemotherapy will have cochlear dead regions and be at high risk for significant speech perception difficulties. Research in participants with hearing loss due to chemotherapy including

both speech perception abilities and cochlear function may provide further insight into the issues these individuals face.

2.6: Speech Perception and Cochlear Damage in Children

In the adults with high-frequency sensorineural hearing loss, it has been suggested that the presence of significant cochlear damage (e.g., cochlear dead region) would require special consideration when providing audibility. There are limited studies currently published which look at the speech understanding of children with significant cochlear damage. Adult studies reveal significant difficulty with word recognition in noise, both in laboratory and real-world settings (Baer et al., 2002, Preminger et al.,

2005). Monro and Malicka (2010) studied word recognition in quiet in children with cochlear dead regions. Researchers reported poorer performance in children with cochlear dead regions as compared to hearing loss matched controls without dead regions. A follow-up study of children with moderate to profound hearing loss supported the finding that children with suspected cochlear dead regions made less efficient use of audible speech components than children without dead regions (Malicka et al. , 2013).

As in the adult literature, there are conflicting opinions on the utility of providing high-frequency audibility to children with significant cochlear dead regions (above 1500

Hz to 2000 Hz). A study of word recognition in quiet in children with cochlear dead regions suggested that they performed more poorly than matched controls without dead regions. No child performed more poorly at the full bandwidth condition suggesting that proving the high frequency information is unlikely to inhibit speech understanding (Monro & Malicka, 2010). A later study by the same authors evaluated children with severe to profound hearing loss and found no improvement in speech understanding when adding high-frequency information (Malicka et al., 2013). A concern within this study is that overlap between the groups was high, suggesting that mean data may not represent the individual participant, a key issue when applying these results to clinical practice. Scollie (2008) noted that in a small sample of children with suspected cochlear dead regions, provision of high-frequency audibility did improve nonsense syllable understanding but to a smaller degree as compared to children with similar hearing loss without suspected cochlear dead regions. Given the potential impact in speech production when limiting high-frequency audibility in children, additional research into speech perception in this population is warranted.

2.7: Assessment of Cochlear Function

Studies by Moore et al. (2000), Moore and Malicka (2013); and Vickers et al.

(2001) suggest that knowledge of severely abnormal cochlear function, specifically

cochlear dead regions, provides insight into speech perception abilities of listeners with high-frequency hearing loss. There is a clear correlation between severely abnormal cochlear function and inability to utlize amplified high-frequency speech information in adults (Baer et al., 2002; Tasell, 1993; Vickers et al., 2001) and in children (Malicka et al., 2009, 2010; Munro et al., 2005). In addition to global speech perception difficulties, participants often had poorer speech perception scores as high-frequency speech access was provided.

Measures of speech perception alone would fail to identify participants with the inability to use high-frequency audibility for improved speech perception. However, clinical researchers do not routinely evaluate cochlear function and speech perception in the same participants. Evaluation of cochlear function in addition to the speech perception of individuals with high-frequency hearing loss would provide additional information on the processes contributing to speech perception and identify individuals who may not benefit from high-frequency audibility. This is particularly useful in listeners with high-frequency hearing loss due to chemotherapy as they may have unique speech perception challenges due to the mechanism of cochlear damage.

Knowledge of this would encourage development of specific rehabilitative options and realistic goals for the individual (Moore, 2004; Robinson et al., 2007).

2.8: Measures of Cochlear Function

(Moore et al., 2000; Sęk et al., 2005) proposed two methods for measuring

cochlear function suitable for clinical implementation. These are the Threshold

Equalizing Noise (TEN) test and Fast Psychophysical Tuning Curves (PTC). Both tools are

purported to identify regions of severely abnormal cochlear function, specifically

cochlear dead regions, where cochlear function is impaired such that transduction of an acoustic signal cannot happen.

2.8.1: Threshold Equalizing Noise Test

To evaluate cochlear dead regions in a clinical setting, Moore et al. (2000)

devised a proprietary masking paradigm using a Threshold Equalizing Noise (TEN)

masker. When presented to participant, TEN masking noise will elevate pure tone

thresholds to the same Sound Pressure Level (SPL) at each test frequency. In frequency

regions where cochlear damage impairs the transduction of the acoustic signal, masked

thresholds will be higher than the level of the TEN masker. High masked thresholds are

then judged as indication of a cochlear dead region in that frequency region (Moore et

al., 2000).

The TEN masker is a band-limited noise spectrally shaped to result in equal

masked thresholds across frequencies. The TEN HL masker will provide equal masked

thresholds in dB HL between 500 to 4000 Hz. TEN HL was created by first determining

the power level required to raise the threshold of a 1000 Hz pure tone to 70 dB HL. For

each additional pure tone frequency (500, 1500, 2000, 3000 and 4000 Hz) the noise

required to equate its threshold to the 1000 Hz tone was determined. TEN HL was

specifically created for clinical use because both the noise and tones can be routed

through a standard audiometer and no conversions are required for determining

threshold in dB HL (Moore et al., 2004).

In clinical application, the TEN level is selected to produce at least 10 dB of

masking at a given frequency, and then masked thresholds are obtained. In normal

hearing participants and in participants with hearing impairment who do not have grossly abnormal cochlear function, the masked threshold will be no greater than 9 dB

above the TEN presentation level (Moore et al., 2004). When masked thresholds are at

least 10 dB above the unmasked thresholds and at least 10 dB above the TEN level,

grossly abnormal cochlear function is indicated at that frequency (Moore et al., 2004). It has been suggested (Malicka et al., 2010) that children with hearing impairment may require a different criterion (e.g., masked thresholds at least 15 dB above TEN level) due to reduced exposure to auditory stimuli. Results of the studies investigating this question have been varied, with some papers suggesting a 10 dB criterion and others suggesting a 15 dB criterion (Malicka et al., 2010, 2013; Moore & Malicka, 2013).

The use of the TEN test in participants with hearing loss due to chemotherapy

may be beneficial in identification of regions of grossly abnormal cochlear function. The

masked threshold task is a tone in noise task and is appropriate for use in even young

children (Malicka et al., 2010) making it appealing for use in this population due to the

potential for additional cognitive delays in participants who have received

chemotherapy (Gurney et al., 2007) .

2.8.2: Fast Psychophysical Tuning Curves

PTCs have been used for many years as a laboratory measure of frequency selectivity (Chistovich, 1957; Small, 1959). In PTC measures, a probe tone is presented

at a low level, and the level of a simultaneous masker (tone or narrow band noise)

required to just mask the probe tone is measured as a function of the masker frequency.

The PTC is “v” shaped with the tip of the “v” typically located near the probe tone. At

low-to-moderate sound levels, the mechanical amplification due to the outer hair cells

provides a significant contribution to the overall tuning curve shape, hence the sharp

tip. The shallow tails on the low frequency side are determined by the passive

mechanical response of the basilar membrane (Sęk et al., 2005).

For individuals with normal hearing and even those with a mild hearing loss, the

masker should be most effective (i.e., “mask” with the lowest intensity) when the

masker center frequency is near the probe tone (Florentine et al., 1980; Glasberg &

Moore, 1986). In a mild hearing loss, the tip of PTC will be at or near, the probe-tone frequency with the entire curve moved higher in intensity. PTCs are wider with greater degrees of hearing loss. Individuals with moderate to severe hearing loss may exhibit greater variability in the PTC shape. The sharpness of the tuning curve is typically altered by intermediate degrees of cochlear hair cell damage (both inner and outer), however the tip remains near the probe tone frequency. In other individuals,

particularly those with a sloping severe-to-profound high-frequency hearing loss, the

tuning curve tip is shifted away from the probe signal frequency towards a lower

frequency (Florentine & Houtsma, 1983; Kluk & Moore, 2005, 2006; Moore & Alcántara,

2001). Here, a masker is most effective not at the probe frequency, but at a lower

frequency. A shift in the tip of the PTC to a frequency away from the probe tone occurs

when cochlear damage at the probe frequency is such that information cannot be

transduced within the frequency range of the probe tone, indicating presence of a

cochlear dead region (Sęk et al., 2005).

The measurement of PTCs is typically completed in the laboratory due to the

time-intensive nature of the task. For example, PTCs routinely can require 1-3 hours to

train a participant, a limiting factor in populations including children and older adults.

To address concerns with the clinical feasibility of obtaining PTCs, a “fast method” using

a swept masker and Békésy tracking was created (Sęk et al., 2005; Sęk & Moore, 2011;

Sęk et al., 2007). The procedure results in a tracing, which is then analyzed in the software using various curve estimation methods in order to determine the tip of the

Fast PTC. A tip shift of greater than 10 to 15%, or conservatively, up to 20% of the probe frequency suggests severe cochlear damage at that frequency (Charaziak et al., 2012;

Glasberg & Moore, 1990; Sęk et al., 2005; Warnaar & Dreschler, 2012). A shift greater

than 20% in school age children indicates a cochlear dead region (Malicka et al., 2009).

The frequency to which the tip of the PTC shifts has been termed the ‘edge frequency’

and is believed to be the first site of at least partially functional neural transmission.

Thus, Fast PTCs determine the frequencies where substantial cochlear damage begins as

opposed to the TEN test, which determines if a given frequency is within a region of

substantial cochlear damage. Determination of the edge frequency may be beneficial in

providing a cut-off for amplification via hearing aids if amplification will be reduced in

regions of substantial cochlear damage.

The Fast PTC method has been validated in the laboratory in both adults and

children (Kluk & Moore, 2005, 2006; Malicka et al., 2009; Munro & Malicka, 2007).

However, Fast PTCs have not been widely utilized clinically in participants with hearing-

impairment (Pepler et al., 2014). As such, additional investigation into the completion

rates and normative data for Fast PTCs, particularly in participants with hearing impairment, is needed.

2.8.3: Fast PTCs and TEN Test Comparison

Fast PTCs and the TEN test have been proposed as clinical methods for

evaluation of cochlear function and for identification of substantial cochlear damage in individuals with hearing-impairment. PTCs (fast and traditional) has often been used as the “gold standard” when measuring frequency selectivity and assessing cochlear function. Initial validation studies of the TEN suggested very close agreement between

TEN and Fast PTC results, suggesting that both methods were equally as effective in identification of regions of substantial cochlear damage (Kluk & Moore, 2005; Moore &

Alcántara, 2001; Moore et al., 2000; Vickers et al., 2001). However, other researchers did not find the same level of agreement, noting that the TEN may overestimate regions of substantial cochlear damage (Summers et al., 2003). It has also been noted that inconclusive test results due to the loud presentation levels of the TEN noise when hearing thresholds were near or above 65 dB HL were a limiting factor in determining the presence of substantial cochlear damage and in determining the reliability of the

TEN test (Hornsby & Dundas, 2009). Warnaar and Dreschler (2012) suggested that that agreement between the two tests may be dependent on the type of cochlear damage and that unique patterns of cochlear damage due to specific etiologies may result in different results between the two tests. However, to this point no research has been published controlling for the etiology of the hearing loss.

Investigation of the cochlear function of participants with hearing loss due to chemotherapy is an important step in evaluating the impact of abnormal cochlear function on speech perception, specifically the utility of high-frequency audibility. In

addition, application of both the TEN test and Fast PTCs in participants with the same

etiology of hearing impairment may provide additional information on the agreement

between the two tests.

2.9: Research Objectives

Despite extensive documentation of the cochlear damage and subsequent hearing loss due to chemotherapy, the speech perception abilities of individuals (both children and adults) with hearing loss due to chemotherapy are largely unexplored.

Individuals with hearing loss due to chemotherapy are likely to have substantial cochlear

damage, and thus greater difficulty with speech perception than the pure tone

audiogram alone would suggest. One purpose of this study was to evaluate the speech

perception abilities of both children and adults with hearing loss due to chemotherapy

for various low-pass filtered noise conditions. Speech perception abilities of normal hearing controls were also assessed and were used to determine a normal range. The speech perception abilities of participants with hearing loss due to chemotherapy were then compared to the normal range.

Evaluation of the cochlear function in individuals with hearing loss due to chemotherapy via psychoacoustic testing provided a mechanism for identification of substantial cochlear damage. The presence of substantial cochlear damage has been proposed as a hallmark for identification of participants unlikely to have improvements in speech perception performance when provided with access to high-frequency speech stimuli. Thus, a connection between measures of cochlear function and presumed cochlear damage was made. Normal hearing participants completed the tasks to determine a normal range of performance. Measures of cochlear function from participants with hearing loss due to chemotherapy were compared with the normal range and participants with abnormal results on measures of cochlear function were identified. Selecting participants with hearing loss due to chemotherapy potentially limited the variability due to the mechanism of damage associated with the TEN test and Fast PTCs and agreement between the two tests were assessed.

Lastly, cochlear function and speech perception are not routinely measured in the same individuals in laboratory research. By evaluating speech perception abilities and cochlear function in the same participants with a known mechanism of cochlear damage, changes in speech perception with increasing high-frequency audibility could

then be compared with measures of cochlear function. A relationship between the measures would suggest that participants who fail to benefit from high-frequency audibility could be identified through the measures of cochlear function utilized. Thus,

beyond typical speech perception measures, clinical assessment of cochlear function would provide additional information important to an individual’s rehabilitation goals.

Chapter 3: Methods

3.1: Participants

Thirty children and fifteen adults with normal hearing participated in the study.

In addition, five children and five adults with hearing impairment also participated in the study. Pediatric participants were between the ages of 7 and 12 years. This age range was selected to best represent a pediatric group with comparable developmental word recognition abilities (Gravel et al., 1999; McCreery & Stelmachowicz, 2011). None of the children had a history of recent middle ear infections, and no child with normal hearing was enrolled in speech therapy services. Normal-hearing children were grouped into three age ranges: 7- and 8-year-olds, 9- and 10- year-olds, and 11- and 12-year-olds with

10 children in each group. Adult participants were between 18 and 64 years of age

(mean age: 24 years). The adult age cut-off was selected due to research suggesting that word recognition in older adults (65+) can begin to decrease due to age effects

(Pichora-Fuller & Singh, 2006).

No participant with hearing impairment had previous experience in hearing research. All participants with hearing impairment had received platinum-based

chemotherapies prior to being enrolled in this study, and all were at least 12 months post-treatment. Participants with hearing loss due to chemotherapy can have

progression of the hearing loss years after treatment and research suggests that the majority of decrease in hearing occurs within the first 12 months after treatment (Brock et al., 2012). Pediatric participants with hearing loss were post-lingually hearing impaired, and none started chemotherapy exposure prior to 12 months of age. Because of the different cancer etiologies and diverse recruitment avenues, a wide range of hearing losses was seen. The names of the platinum-based chemotherapies significant to this study were identified; however, information including cumulative dosage, timing of intervention and additional medications were not collected. Table 1 presents the demographic data for the participants with hearing impairment, including sex, age, ear tested, cancer diagnosis and type of chemotherapy (if known). Figure 1 contains the individual thresholds for the adults with hearing impairment and the normal hearing range shaded in gray. Figure 2 shows the same information for the children with hearing impairment.

Table 1: Sex, age, ear tested, type of cancer, and type of intervention for individual participants with hearing impairment.

Participant Sex Age Ear Cancer diagnosis Intervention

Adults 1 F 49y 1m L Tonsil Cancer Cisplatin/Radiation Left

2 F 56y 10m L Breast Cancer Cisplatin

3 M 21y 10m L Testicular Cancer Cisplatin/ Carboplatin

4 M 52y 1m L/R Medulloblastoma Cisplatin/Radiation Left 5 M 61y 11m L/R Throat Cancer Cisplatin/Radiation Right

Children 1 M 12y 6m R Medulloblastoma Cisplatin/ Carboplatin

2 F 10y 8m L Medulloblastoma Cisplatin/Carboplatin

3 F 10y 8m R Osteosarcoma Cisplatin

4 M 7y 10m L Neuroblastoma Cisplatin 5 F 8y 0m R Hepatoblastoma Cisplatin

Figure1: Pure tone thresholds are provided for the adults with hearing impairment. The grey shaded area represents normal hearing. Red symbols indicate right ear and blue symbols indicate left ear.

Figure 2: Pure tone thresholds are provided for the children with hearing impairment. The grey shaded area represents normal hearing. Red symbols indicate right ear and blue symbols indicate left ear.

3.2: Participant Recruitment and Scheduling

Most adults with hearing impairment were recruited from The Arthur G. James

Cancer Hospital and Richard J. Solove Research Institute. All children with hearing

impairment were recruited through either the oncology or the audiology departments

at Nationwide Children’s Hospital. Both hospitals are in Columbus, Ohio. Normal- hearing participants were recruited through social media postings (e.g., Facebook, Study

Search) and classroom announcements. Most of the adults with normal hearing were recruited through The Ohio State University (OSU) Department of Speech and Hearing

Science. Data collection ran from December 2015 through July 2017.

Each experimental session lasted approximately two hours (including breaks as

necessary) and each participant required one or two sessions to complete all tasks. All

sessions took place in a sound-treated booth in either the OSU Department of Speech

and Hearing Science or the Nationwide Children’s Hospital Department of Audiology.

Participants were paid for their participation. Informed consent was obtained from all

adult patients and guardians of minor participants. All minor participants provided

assent prior to beginning the study. All study procedures were reviewed and approved by the Ohio State University and Nationwide Children’s Hospital Institutional Review

Boards.

3.3: Materials and Procedures

3.3.1: Pure Tone Thresholds

3.3.1.1: Pure Tone Stimuli

Air Conduction pure tone thresholds were measured at octave frequencies from 250 to 8000 Hz and inter-octaves 1500, 3000 and 6000 Hz. Bone conduction thresholds were measured using a BC10 Bone oscillator. Bone conduction pure tone thresholds at octave frequencies 500 to 4000 Hz were measured in participants with hearing impairment.

3.3.1.2: Pure Tone Threshold Procedure

Hearing thresholds were measured first at the initial session. Thresholds were measured in each ear with a standard clinical audiometer (GSI-61 or GSI AudioStar Pro) using the Hughson Westlake procedure for all participants. Air conduction thresholds were measured using supra-aural earphones.

Control participants had air conduction thresholds lower than 20 dB HL at all frequencies. Hearing-Impaired participants had pure tone thresholds less than or equal to 20 dB HL between 250 and 1000 Hz and greater than 20 dB HL above 2000 Hz.

Participants were excluded from the study if a conductive component of 15 dB or greater was seen at any frequency. 41

3.3.2: Word Recognition

3.3.2.1: Word Recognition Stimuli

Recorded speech word lists including The Northwestern University Auditory Test

Number 6 (NU-6) (Tillman & Carhart, 1966) and The Central Institute for the Deaf (CID)

W-22 (Hirsh et al., 1952) were used to establish baseline word recognition in quiet for

participants with hearing impairment. Recorded word lists were either presented via compact disc (CD) (at Ohio State University) or as preloaded speech stimuli on the audiometer (at Nationwide Children’s Hospital).

3.3.2.2: Word Recognition Procedure

Word Recognition testing was completed only by participants with hearing impairment during the first session. Recorded speech lists of 50 words per list were presented via either a CD routed through a GSI 61 audiometer (at OSU) or directly through a GSI AudioStar Pro Audiometer (at Nationwide Children’s Hospital).

Participants wore supra-aural earphones. Stimuli were presented at a level of 40 dB SL or at the participant’s reported most comfortable level if 40 dB SL was reported as being too loud. A percent correct score was recorded for each ear.

3.3.3: Threshold Equalizing Noise Test

3.3.3.1: TEN Test Stimuli

Pure tone stimuli included 500, 1000, 2000, and 4000 Hz for normal-hearing control participants and 500, 1000, 2000, 3000 and 4000 Hz for participants with hearing impairment. TEN noise is used to provide equal masked thresholds in dB HL for pure tones between 500-4000 Hz (Moore et al., 2004)

3.3.3.2: TEN Test Procedure

TEN testing was completed at the first session for all participants. The TEN HL test stimuli were presented via either a CD routed through a GSI 61 audiometer (at OSU) or directly through a GSI AudioStar Pro Audiometer (at Nationwide Children’s Hospital).

Participants wore TDH-39 headphones. The order of test frequencies was randomized for each participant. Unmasked pure tone thresholds using the TEN test pure tone stimuli were obtained at each frequency in each ear. Masked pure tone thresholds were obtained using a modified Hughson Westlake procedure with a 2-dB step size

(described in Moore & Malicka, 2013).

For normal-hearing control participants, masked pure tone thresholds were obtained at three TEN intensity levels (30, 50 and 70 dB HL). For participants with hearing impairment, the level of the TEN masked varied for each participant and 43

depended on the unmasked pure tone threshold. The level of the TEN masker was at least 10 dB HL above the unmasked pure tone thresholds had to be at least 10 dB below the TEN level. Thus, if the unmasked pure tone threshold was 40 dB HL, masked thresholds were obtained at TEN intensities of 50 dB HL and 70 dB HL or if unmasked pure tone threshold was 60 dB HL the masked threshold was obtained at a TEN level of

70 dB HL. When unmasked pure tone thresholds were 70 dB HL or greater, the TEN was introduced at 10 dB SL, with a limit of 95 dB HL. When a participant’s unmasked threshold at 4000 Hz exceeded the limits of the audiometer or when the masked threshold at 4000 Hz suggested the presence of substantial cochlear damage at 4000 Hz,

3000 Hz was used. Likewise, if unmasked thresholds at 2000 Hz exceeded the audiometer or suggested the presence of substantial cochlear damage, 1500 Hz was used. Masked thresholds in dB HL were recorded at each frequency and TEN intensity level.

3.3.4: Fast Psychophysical Tuning Curves

3.3.4.1: Fast PTC Stimuli

The Fast PTC software developed by Sęk, & Moore (2011) was installed on a laptop running Windows 7 with a Realtek Audio soundcard. Presentation was via

Sennheiser HD215 headphones calibrated according to directions provided within the software. Pulsed pure tones (200 ms duration) were presented simultaneously with a

continuous narrow band noise masker. The bandwidth of the masker noise was

selected based on previous research designed to prevent beat detection. The

bandwidth was 100 Hz for a 500 Hz probe tone, 200 Hz for the 1000 Hz probe tone and

was 320 Hz for the 2000, 3000, and 4000 Hz probe tones, and (Kluk & Moore, 2005,

2006). Since high-frequency cochlear damage was likely within the participant pool, the masker sweep direction was set to increasing frequency. Using an upward sweep results in a more conservative measure of downward tip shift, which is indicative of cochlear damage at that frequency (Sęk & Moore, 2011; Sęk et al., 2007). A continuous

low-pass noise was also presented at 40 dB SPL to limit the potential for detection of

combination tones. The bandwidth of the low-pass noise was determined by the

software to mask potential combination tones. The maximum output of pure tone and

masker intensities was limited to 95 dB SPL in the software.

3.3.4.2: Fast PTC Procedure

Fast PTCs were obtained over one or two sessions. In control participants, the

ear tested was randomized so that eight left ears and seven right ears were tested in

adults and an equal number (15) of left and right ears were tested in children. For

participants with hearing impairment, the ear with the greater degree of high-frequency

hearing loss was initially selected. In two participants with hearing impairment, the second ear was also tested due to a notable asymmetry between ears.

Normal-hearing participants were tested using pure tone stimuli of 500, 1000,

2000, and 4000 Hz. In participants with hearing impairment, potential pure tone stimuli included 500, 1000, 2000, 3000 and 4000 Hz. The Fast PTC clinical procedure recommends selection of a single pure tone closest to and just above the suspected edge frequency of substantial cochlear damage. Thus, frequencies were chosen for each participant with hearing impairment based on the thresholds in that ear.

Previous studies suggested use of a 10 dB SL probe tone level (Sęk & Moore,

2011). However, the initial control participants reported difficulty in hearing the probe tone at this level and were unable to complete a trial. For that reason, the probe tone was set at 30 dB SPL when pure tone thresholds were 20 dB HL or lower for all participants. This level approximates 20 dB SL when hearing thresholds are within normal hearing limits. When hearing was not within normal limits, threshold was determined using the Fast PTC software. Based on this threshold, a pure tone presentation level of 20 dB SL was used. Again, this presentation level was determined after preliminary data revealed that the previously recommended 10 dB SL was not sufficient for most individuals to complete a trial. For all participants, the initial masker intensity was determined by the software, based on the probe-tone presentation level.

The Fast PTC program uses a Békésy threshold-tracking procedure where participants pressed the space bar on a keyboard to indicate when the target tone was heard and released the space bar when the target tone was no longer heard. The intensity level of the masker automatically increased when the space bar was pressed and decreased when the space bar was released. Previous research suggested use of either a 1 dB/sec or 2 dB/sec rate of change (Malicka et al., 2009; Pepler et al., 2014).

However, other work suggested that tip estimates are more variable with the smaller step size (Warnaar & Dreschler, 2012) and pilot data in children suggested that the rate of 2 dB/sec resulted in the most reliable and usable PTCs, thus 2 dB/sec step changes were used. The time to complete each individual PTC trial was three minutes with the rate change of the center frequency of the masker noise dependent on the pure tone stimulus frequency. The order of test frequencies was randomized for each participant.

Two trials at each frequency were run and the average tip frequency obtained. A third trial was attempted if the tip frequency could not be determined on either of the previous two runs.

The Fast PTC software plots the resulting PTC at the end of each run. Figure 3 is a screen shot of one representative plot produced by the program. It shows a PTC for a

2000 Hz probe tone presented at 30 dB SPL for the left ear of normal-hearing adult participant 11. Each tuning curve was later reviewed using recommended acceptance criteria (Myers & Malicka, 2014). All tuning curves meeting the acceptance criteria were

Figure 3: Raw data for a 2000 Hz PTC presented at 30 dB SPL for the left ear of normal-hearing adult participant 11. The green dot indicates the probe intensity level and frequency.

analyzed using the five available curve fitting procedures to determine the estimated tip

frequency (Sęk et al., 2005, 2007; Sęk & Moore, 2011). Appendix A describes and illustrates the five different approaches to tip-frequency estimation. Acceptable PTCs were analyzed via the five curve fitting procedures to obtain tip frequency estimates for each procedure. The success rate, determined by the number of tuning curves that meet acceptance criteria, was determined. In addition, participant repeatability within a single session was determined.

3.3.5: Speech Perception

3.3.5.1: Speech Perception Stimuli

The 75-sentence list from the Multimodal Lexical Sentence Test (MLST) for children (Kirk et al., 2012) was recorded by a female talker with Midwest dialect (the

author). Sentences were recorded digitally in a sound booth using a Logitech headset

with boom microphone. Sentences were sampled at a rate of 44.1k Hz and group

normalized to the average level of the source files (0 dB) via Adobe Audition 3.0.

Sentences were then low-pass filtered using a 10th order Butterworth filter provided

within Adobe Audition 3.0 at four cut off frequencies: 1000, 2000, 4000, and 6000 Hz

using a 10th order Butterworth frequency. A broadband noise stimulus was created

and shaped via fast Fourier transform to match the long-term average speech

spectrum (LTSS) of the combined sentence tokens for each cut-off frequency (including

full bandwidth). The speech-spectrum shaped noise was then added to each cut-off

frequency condition to generate the following SNR: +3 dB, 0 dB, -3 dB. This resulted in

15 conditions: five cut-off frequency conditions X 3 SNR conditions. The 75 sentence

MLST was randomized three times to make three different ordered lists. Each randomization of 75 sentences was assigned to a SNR condition (+3 dB, 0 dB, -3 dB).

The three lists were then broken into five sets of 15 sentences each. Pilot data

collected using normal-hearing control participants found no significant differences in

percent correct between the five sets of 15 sentences under different frequency conditions. In addition, pilot data in children with normal hearing, as well as published results by Silberer et al. (2015) suggested that the three SNR values would provide a reasonable range of speech perception performance. For each participant, within the three SNR conditions, each frequency condition was randomly assigned to one of the five sets of 15 sentences. This resulted in all frequency conditions being represented as a 15-sentence block within the larger 75-sentence list. Participants then heard each sentence only three times across the various experimental conditions; thus, limiting the potential for learning the sentences.

3.3.5.2: Speech Perception Verification of Audibility

Speech perception testing of all participants was completed using a premium digital behind-the-ear hearing aid coupled to the ear via an occluding foam mold

(Comply tip). Directional microphones, feedback managers and noise reduction algorithms were disabled. Audibility was defined as access to the speech stimuli at a given frequency and intensity. Audibility of the speech stimuli was provided via amplification for participants with hearing impairment.

In order to ensure appropriate audibility, the hearing aid was programmed to

Desired Sensation Level (DSL) 5.0 child prescriptive target based on the participant ’s

hearing thresholds and age (Scollie et al., 2005). Hearing aid output was verified using simulated real ear test box measures on the Audioscan Verifit. Examples of the Verifit speech-mapping screen for both a participant with normal hearing and a participant with hearing impairment is presented in Appendix B. Hearing aid output was adjusted via NOAH 4 programming software to match DSL 5.0 child targets for 65 dB SPL calibrated female speech stimuli inputs and to ensure that Maximum Power Output

(MPO) was below established limits. The female speaker was used for establishing target amplification because the study speech stimuli were produced by a female speaker and the medium speech input is calibrated to a 65 dB SPL level, the same level of the study speech stimuli. Live Speechmapping was then selected and the full bandwidth study speech stimuli (speech only, no noise) were presented via Direct Audio

Input with laptop volume settings locked at a previously determined volume out. The hearing aid output was adjusted to match the previously established DSL 5.0 child targets for at 65 dB SPL speech input. The settings were then saved to the hearing aid.

In normal-hearing control participants, the full bandwidth speech condition provides audibility through approximately 8000 Hz, after which little to no high frequency information exists. Because of this, 8000 Hz is used as the cut-off frequency for normal-hearing control participants.

To determine the audibility limits in participants with hearing impairment, two frequency points were established. Full audibility was defined to be the highest

frequency at which the lower edge of the spectrum was 5 dB above the participant’s threshold. Partial audibility was determined to be the highest frequency at which the midpoint of the speech spectrum was 5 dB above the participant’s threshold.

3.3.5.3: Speech Perception Procedure

Speech perception was completed over one or two sessions. Each of the 15 conditions was presented using the digital behind-the-ear hearing aid connected via direct audio input to a laptop running Adobe Audition. Participants were asked to repeat as much as possible of each sentence heard. For each sentence, three target words were scored. The percent correct of the target words correctly identified for each condition (out of a possible 45 words) was calculated.

Chapter 4: Results

4.1: Participants with Normal Hearing

4.1.1: Speech Perception in Adults and Children

Preliminary data in children with normal hearing suggested developmental

trends in speech perception performance across conditions (i.e., younger children

performed more poorly than older children). However, after increasing the total

number of child participants in each age group, this trend did not continue and an

analysis of variance (ANOVA) did not reveal any statistically significant differences

between age groups (F 2,27 = 0.14, p > 0.05). Given this, data across age groups were collapsed for subsequent analysis.

Figures 4 and 5 plot the average number of words correctly identified per condition as a percent correct (± 1 standard deviation) at each SNR and low-pass filter

condition for adults and children respectively for the MLST. The green circles and line

indicate the average percent correct across low-pass filter cut-off frequency for the +3

dB SNR condition. The blue triangles and line indicate the 0 dB SNR condition, and the

red squares and line indicate the –3 dB SNR condition. Figure 6 shows adult (black) and 53

child (color) results plotted together. Mean speech perception performance for both

adults and children increased as additional acoustic information was provided via higher

low-pass filter cut-off frequency and with improved SNR.

Mean speech perception performance for adults was better than for pediatric

participants at each SNR and low-pass filter frequency condition. For the adults, near

ceiling performance (~100%) occurred as early as the 4000 Hz low-pass filter frequency

condition in both the 0 and +3 dB SNR conditions. Children continued to show improved

speech perception through the 8000 Hz low-pass filter frequency condition for all SNR

conditions. In contrast, some children were unable to correctly identify a single correct

target word and were at floor performance (0%) up to and including the 4000 Hz low-

pass filter frequency condition in the most challenging (-3 dB) SNR.

For statistical analysis, the total number of words correctly identified for each

SNR and low-pass filter frequency condition were converted using Studebaker’s rationalized arcsine transform (Studebaker, 1985). Note that statistical analyses were

conducted using transformed scores and all figures and tables show the number of

target words identified as percentage correct. A mixed model ANOVA was used to

investigate the differences in speech perception performance with age as the between-

subject variable and frequency and SNR as within-subject variables. For all statistical

analysis, an a priori alpha level of 0.05 was used with the Greenhouse-Geisser correction

when evaluating significance. One normal-hearing adult participant (#6) had speech

perception scores that fell more than two standard deviations below the normal hearing average and was therefore considered an outlier. The ANOVA results did not change when completed both with and without this participant’s data, therefore this

participant’s data were included.

Average words correctly per correctly identified words Average

: Figure 5 condition aspercent a correct speech score1 (± SD) at with children for condition frequency and SNR each normal usingMLST. hearing the with

adults

Average words correctly per correctly identified words Average

Figure 4: condition aspercent a correct speech score1 (± SD) at for condition frequency and SNR each normal usingMLST. hearing the

Statistical results confirm a significant main effect for age (F 1,43 = 39.99, p < 0.05).

Adults had significantly better speech perception performance as compared to children at all filter conditions and across all SNR. The analysis also confirmed a significant main effect of both low-pass filter frequency cut-off (F 2.98, 127.99 = 592.44, p < 0.05) and SNR

(F1.54,66.07 = 357.5, p < 0.05). Post-hoc paired comparisons with Bonferroni correction (p

< 0.003) confirmed significantly better speech perceptions performance across all low-

pass filter frequency conditions as SNR improved from -3 dB to 0 dB to +3 dB. Paired

comparisons between low-pass filter frequencies revealed a significant improvement as

low-pass filter frequency increased except for children between 8000 vs 6000 Hz in the

+3 dB SNR condition and for adults between 8000 vs 6000 Hz and 6000 vs 4000 Hz in the

+3 dB SNR condition and 6000 vs 4000 Hz in the -3 dB SNR condition.

Statistical analysis indicated a significant interaction for SNR*Frequency

(F 5.04,217.3 = 9.51, p < 0.05). The significant interaction was due to the smaller gains in speech perception with increasing low-pass filter frequency cut-off in the -3 dB SNR

condition as compared to the same low-pass filter frequency cut-off conditions at the 0

and +3 dB SNR conditions. In addition, there was a significant two-way interaction of

Frequency*Age (F 2.98,127.99 = 6.19, p < 0.05). This interaction is driven by the larger gains in speech perception made by adults as compared to children as the filter cut-off increased from 1000 Hz to 2000 Hz and 2000 Hz to 4000 Hz.

Finally, there was a statistically significant three-way interaction between SNR,

Frequency and Age (F 5.05,217.3 = 2.77, p < 0.05). This indicates that the interaction

between SNR and low-pass filter frequency cut-off was different between adults and children. Specifically, speech perception performance in children showed smaller gains in speech perception in the -3 dB SNR condition, particularly at lower frequency cut-offs, as compared to adults.

To identify participants with abnormal speech perception performance, the percent correct data for both adults and children were used to determine a range of normal-hearing performance. The range of normal-hearing performance was based on the average speech score ± 2 standard deviations for each SNR and filter condition.

Recall that Figures 4 and 5 plot the average speech score (± 1 standard deviation) at each SNR and frequency condition for adults and children respectively. Note that within normal-hearing control participants (adult and child), only one adult participant fell outside this range for more than one condition.

4.1.2: Threshold Equalizing Noise Test

Results of the TEN test for adults and children with normal hearing are shown in

Figures 7 and 8 respectively. Results are shown in tabular form in Appendix C. All adults

and children with normal hearing could complete the tasks required for the TEN HL test

at all frequencies and intensities. An ANOVA did not reveal any statistically significant

differences between age groups (F 2,55 = 2.63, p > 0.05), thus pediatric data was combined.

Average adult masked thresholds were at or below TEN presentation levels across all frequencies and intensities. Average pediatric masked thresholds were within

±1 dB of TEN presentation levels. To determine if a significant difference existed between adult and child data, the difference between each masked threshold and the

TEN presentation level was found for each participant across conditions. A mixed model

ANOVA was used to examine the data with age as the between-participants factor and frequency and intensity as the within-participant factors. The ANOVA revealed a significant main effect for age (F1,86 = 26.16, p < 0.05) confirming that the adult masked

thresholds were significantly lower than the child masked thresholds. Although the

masked thresholds for adults were lower than for the children, there was never more

than a 2 dB difference between the adult and child averages, which is less than a single

step size in the testing procedure. Thus, although statistically significant, the difference

between groups would not be clinically significant.

masked

child hearing hearing - Average normal Average

Figure 8: TEN HL dB 70 50 and 30, for SD) (+2 threshold Hz. 4000 2000 and 1000, 500, at levels presentation

hearing adult masked masked adult hearing - 50 and 70 dB HL TEN TEN HL dB 70 50 and

Average normal Average

Figure 7: 30, for SD) (+2 threshold Hz. 4000 2000 and 1000, 500, at levels presentation

Across all frequencies, no masked threshold was more than 6 dB above the TEN

presentation level for either the adults or children. In fact, a masked threshold more

than 6 dB above TEN presentation level would be greater than two standard deviations

above average masked thresholds for all intensity levels at each frequency tested.

Previous research has used this upper limit (the difference between the masked

threshold and the TEN presentation level) to establish the criterion for determining an abnormal masked threshold in individuals with hearing impairment (Malicka et al., 2010;

Moore et al., 2004). Moore et al. (2000) proposed that abnormally high masked thresholds are suggestive of a region of substantial cochlear damage and may indicate a cochlear dead region in the most severe cases of damage, thus determination of an abnormally high masked threshold is needed. Results from this study suggest that a masked threshold of more than 6 dB above TEN presentation level is outside of normal limits and may be indicative of substantial cochlear damage in both adult and pediatric participants. This is smaller than previously published data which typically suggests thresholds more than 10 to 15 dB are indicative of substantial cochlear damage (Moore et al., 2000; Summers et al., 2003).

4.1.3: Psychophysical Tuning Curves in Adults with Normal Hearing

All adults with normal hearing were able to complete two PTCs at each frequency (500, 1000, 2000 & 4000 Hz) for a total of 120 PTCs. Four participants did require a third trial at 4000 Hz to obtain an accurate PTC and two participants required a third trial at 1000 Hz. Otherwise, adult participants did not require additional training or trials to be able to complete the test.

The Fast PTC software provides five different methods for tip frequency

estimation, resulting in eight total estimates (three estimates are provided by the

double low-pass filter method and two are provided via the moving average). Initial

evaluation of each tuning curve was made using published acceptance criteria (Myers &

Malicka, 2015; Sęk, & Moore, 2011). However, this resulted in many tuning curves

being rejected, even when a clear tip frequency could be identified. As the published

acceptance criteria seemed likely to eliminate usable data and artificially reduce the

variability in the participant population, modifications were made to the acceptance

criteria. Examples of results for the current study that violate the criteria are shown in

Appendix D. Within this study, the level difference criterion was used only when level

differences greater than approximately 45 dB were present. A smaller value would have

resulted in a large number (nearly 25%) of otherwise acceptable PTCs being rejected.

The results of this study thus included a number of tuning curves with few reversals.

This reduced the ability of the software to calculate the tip frequency using the Double

Linear Regression and Ro Ex methods and contributed to the missing data within the two methods. If a viable PTC was obtained with a clear tip frequency, the values of the tip frequency estimates were used whenever provided by the software.

In some cases, a tip frequency estimate could not be made. This typically occurred when there were too few reversals on one side of the tuning curve. Table 2 lists the method of tip frequency calculation and the number of estimates obtained at each frequency. Thirty tuning curves were obtained at each frequency. All but three methods provided estimates 100% of the time, with the Quadratic Function providing estimates 93.3%, double linear regression providing estimates 92.2% of the time and the

Ro Ex method providing an estimate only 74.2% of the time.

Table 2: Success rate of each tip estimate method by frequency in adults.

Method 500 Hz 1000 HZ 2000 HZ 4000 HZ

Double Linear Regression 96.67% 100% 96.67% 76.67%

2pt Moving Average 100% 100% 100% 100%

4pt Moving Average 100% 100% 100% 100%

Quadratic Function 100% 100% 100% 73.33%

Double Low-Pass.25 100% 100% 100% 100%

Double Low-Pass.20 100% 100% 100% 100%

Double Low-pass.15 100% 100% 100% 100%

RoEx 73.33% 86.67% 70% 67.67%

The percent error for each PTC using all eight methods was calculated by finding the difference between the tip frequency estimate and the probe tone frequency divided by the probe tone frequency. Negative numbers indicate that the tip frequency falls below the probe tone while positive numbers indicate the tip frequency is higher than the probe tone. Given the use of an upward sweeping band-pass masker, it is expected that the tip frequency may be shifted slightly above the probe tone due to the test method. Table 3 lists the mean, standard deviation and minimum tip frequency error for each method at each frequency.

Table 3: Success rate of each tip estimate method by frequency in adults.

500 Hz 1000 Hz 2000 Hz 4000 Hz Overall Method

Double Linear Regression Average 5.50% 4.02% 4.49% 8.78% 5.70% SD 3.91% 3.01% 1.72% 4.75% 3.53% Min 0.60% -2.10% 0.00% -3.10% -3.10% 2 Point Moving Average Average 3.97% 2.67% 1.72% 4.82% 3.30% SD 4.23% 3.17% 2.83% 3.96% 3.59% Min -5.00% -3.30% -2.60% -4.33% -5.00% 4 Pont Moving Average Average 3.83% 2.86% 2.15% 5.50% 3.59% SD 3.50% 2.86% 2.43% 3.51% 3.11% Min -4.80% -3.10% -1.45% -0.58% -4.80% Quadratic Function Average 4.22% 0.12% -0.57% 0.16% 0.98% SD 2.39% 1.77% 1.90% 5.08% 3.09% Min 1.00% -3.10% -4.40% -5.60% -5.60% Double Low-Pass .25 Average 4.81% 2.94% 2.40% 6.09% 4.06% SD 3.48% 2.84% 2.16% 3.32% 2.99% Min -2.80% -4.10% -2.30% 1.05% -4.10% Double Low-Pass .20 Average 5.61% 2.56% 2.34% 5.47% 4.00% SD 4.07% 2.25% 2.00% 3.55% 3.09% Min -2.80% -1.60% -2.15% -2.58% -2.80% Double Low-Pass .15 Average 6.03% 2.83% 2.04% 3.24% 3.54% SD 3.71% 2.14% 1.98% 5.41% 3.59% Min -0.80% -1.60% -2.15% -7.78% -7.78% RoEx Average 7.25% 5.12% 5.79% 8.31% 6.62% SD 4.37% 3.43% 2.16% 3.86% 3.55% Min 0.80% -0.60% 3.35% 2.65% -0.60%

The Quadratic Function method provided the smallest error measurements at

1000, 2000 & 4000 Hz and had the smallest overall error measurement of 0.98%. This is not surprising since the developers of the Fast PTC software noted in early papers that some methods provided better tip frequency estimates at a given frequency than others

(Sęk et al., 2005). The two methods with the largest error measurements, Double Linear

Regression and RoEx, were also the two most likely to fail to produce a tip frequency estimate. Of the two methods with the smallest error measurements, the Two-Point

Moving Average provided estimates for all tuning curves as compared to the Quadratic

Function with provided an estimate 93% of the time.

Reliability was evaluated by obtaining the difference between the two error measurements for each frequency. Table 4 lists the number of sets of PTCs used (as noted previously, not all methods provided data for each PTC) and the mean and standard deviation for each method. The Quadratic Function had the lowest average difference between trials for 500 Hz, 1000 Hz, and 2000 Hz. However, it also had the largest average difference between trials for 4000 Hz. The smallest average difference between trials across all four frequencies was 1.93%, given by the Quadratic Function.

Table 4: Number of PTC pairs, average error difference and standard deviation between PTC pairs for each tip-frequency estimation method at each frequency in adults.

500 Hz 1000 Hz 2000 Hz 4000 Hz

Double Linear Regression N=14 N=14 N=14 N=10 Average 2.70% 2.70% 2.22% 2.30% SD 2.78% 2.78% 1.56% 2.05% 2pt Moving Average N=15 N=15 N=15 N=15 Average 4.84% 3.25% 2.92% 2.94% SD 5.42% 2.44% 2.35% 2.45% 4pt Moving Average N=15 N=15 N=15 N=15 Average 3.77% 2.53% 1.68% 2.59% SD 4.05% 3.03% 1.41% 1.94% Quadratic Function N=15 N=15 N=15 N=10 Average 1.40% 1.32% 0.96% 4.05% SD 0.93% 1.64% 1.03% 4.66% Double Low-Pass .25 N=15 N=15 N=15 N=15 Average 3.73% 2.43% 2.53% 3.30% SD 3.29% 1.82% 1.64% 2.34% Double Low-Pass .20 N=15 N=15 N=15 N=15 Average 4.49% 2.09% 2.50% 3.23% SD 2.66% 1.02% 1.81% 2.13% Double Low-Pass .15 N=15 N=15 N=15 N=15 Average 2.91% 2.24% 2.49% 3.32% SD 2.11% 1.60% 1.69% 2.95% RoEx N=8 N=14 N=8 N=8 Average 2.43% 3.99% 1.61% 4.07% SD 1.87% 2.36% 1.98% 3.01%

4.1.4: Psychophysical Tuning Curves in Children with Normal Hearing

Greater variability is seen in the pediatric data, beginning with the ability to complete the task. Pilot data suggested that most children could complete PTCs for two frequencies within a test session. To obtain a wider range of frequency information, children were randomly assigned two frequencies initially. If a child was not able to produce acceptable PTCs for one of the first two trials at a given frequency, a third trial was attempted. If participants were unable to produce an acceptable tuning curve in either of the two trials, a third was not attempted. Based on time and fatigue level, some children were able to complete additional frequencies beyond the two initially assigned.

All children were able to produce at least one acceptable tuning curve. Twenty- eight of the children were able to produce two acceptable tuning curves at a single frequency (used for reliability measures). Twenty-one of the children were able to produce two acceptable tuning curves at two frequencies. Two children could produce only a single acceptable tuning curve. The two children able to produce only a single acceptable PTC were both in the youngest age group; however, there were children in all age groups who were unable to provide more than one set of acceptable PTCs.

Overall, the number of possible trials for each frequency was similar for 1000 Hz,

2000 Hz and 4000 Hz (26-27 times) but less for 500 Hz (20 times). The difference in total

number of trials was due to the different completion rates across frequencies.

Nevertheless, a similar percentage of each age group is represented at each frequency.

The total number of acceptable tuning curves varies by frequency. Table 5 lists the total number of tuning curves attempted and the percentage of acceptable tuning curves for each frequency. As in the adult population, but to a much greater extent, children had

difficulty producing an acceptable tuning curve at 4000 Hz.

Table 5: Total number of PTCs attempted at each frequency and the overall success rate in children.

500 Hz 1000 Hz 2000 Hz 4000 Hz

Total Trials 45 57 53 62

Percentage Acceptable 75.6% 84.2% 84.9% 66.1%

All acceptable tuning curves were then analyzed in the same way as the adult

data. It was expected that certain methods would fail to provide a tip frequency

estimate more frequently in the pediatric data because pediatric tuning curves generally

had fewer reversals with longer runs, which limits the ability of some methods to

generate a tip frequency estimate. However, this was not case as can be seen in Table 6

(like Table 2 in the adult data). Table 6 lists the method of tip frequency calculation and

the number of estimates obtained at each frequency. The total number of acceptable

tuning curves is noted next to the frequency. As in the adult data, all but three methods

provided estimates 100% of the time. The Quadratic Function provided estimates 94.6%

of the time, Double Linear Regression provided estimates 89.9% of the time and the Ro

Ex method was again the least likely to provide an estimate, here 76.2% of the time.

Table 6: Success rate of each tip estimate method by frequency in children.

Method 500 Hz 1000 Hz 2000 Hz 4000 Hz

N=34 N=48 N=45 N=41

Double Linear Reg 85.3% 91.7% 91.1% 90.2%

2pt Moving Average 100% 100% 100% 100%

4pt Moving Average 100% 100% 100% 100%

Quadratic Function 94.1% 97.9% 100% 87.8%

Double Low-Pass .25 100% 100% 100% 100%

Double Low-Pass .20 100% 100% 100% 100%

Double Low-Pass .15 100% 100% 100% 100%

RoEx 76.5% 77.1% 84.4% 65.9%

The percent error for each PTC using all eight different methods was calculated for the pediatric data. Table 7 (like Table 3 in the adult data) lists the mean, standard deviation and maximum and minimum tip frequency error for each method at each frequency.

Overall, error measurements were notably higher with greater variability and larger minimum and maximum error values in the pediatric data as compared to the adult data. In addition, the most appropriate method (lowest error measurement) varied depending on frequency. The Two-Point Moving Average provided the lowest error measure at 500 Hz and 2000 Hz and the Quadratic Function provided the lowest error measure at 1000 Hz and 4000 Hz. As in the adult data, the Quadratic Function provided the lowest error measurement with an overall average of 4%. The Double

Linear Regression method had the highest average error measurement of 6.2%.

Table 7: Mean, standard deviation, and minimum tip frequency error for each method at each frequency in children.

500 Hz 1000 Hz 2000 Hz 4000 Hz Overall Method

Double Linear Regression Average 5.5% 6.9% 4.4% 7.9% 6.2% SD 8.3% 6.7% 4.7% 7.7% 7.0% Min -12.6% -14.6% -13.7% -11.5% -14.6%

2 Point Moving Average Average 2.7% 6.7% 2.2% 5.4% 4.2% SD 8.0% 7.6% 4.2% 5.8% 6.6% Min -15.2% -10.4% -11.0% -5.7% -15.2%

4 Point Moving Average Average 4.6% 6.6% 2.4% 4.9% 4.6% SD 8.4% 7.8% 4.3% 5.6% 6.7% Min -10.8% -12.1% -10.7% -5.4% -12.1%

Quadratic Function Average 5.3% 4.6% 2.7% 3.2% 4.0% SD 6.7% 7.2% 4.6% 7.3% 6.6% Min -17.6% -12.3% -5.0% -8.5% -17.6%

Double Low-pass .25 Average 5.0% 6.3% 3.2% 5.0% 4.9% SD 8.0% 8.3% 6.9% 5.6% 7.3% Min -11.0% -11.8% -10.3% -5.3% -11.8%

Double Low-pass .20 Average 5.3% 6.1% 3.4% 5.4% 5.0% SD 7.7% 8.0% 7.4% 5.6% 7.3% Min -10.4% -11.8% -10.3% -5.3% -11.8%

Double Low-pass .15 Average 5.4% 7.9% 4.1% 4.2% 5.4% SD 7.5% 11.2% 8.1% 11.9% 9.9% Min -8.8% -11.8% -10.3% -49.9% -49.9%

RoEx Average 4.3% 3.7% 6.3% 5.9% 5.1% SD 6.4% 6.9% 4.0% 5.6% 5.8% Min -8.8% -16.8% -1.2% -4.4% -16.8%

Reliability was evaluated by obtaining the difference between the two error

measurements for each frequency. Given that not all children were able to provide two

acceptable tuning curves at a given frequency, the number of pairs of PTCs used for

determining the difference between trials varies by frequency. Table 8 lists the number

of sets of PTCs used (as noted previously, not all methods provided data for each PTC),

the mean and standard deviation of this difference between the two PTCs as well as an

overall average for each method for the pediatric data (as in Table 4 for adults). The

average differences between trials for children are higher across all frequencies as

compared to adults. This suggests greater variability and less consistency between trials

for a given frequency. The lowest overall difference between trials was 5.6% for the

Quadratic Function.

One purpose of the current research was to determine the range of tip

frequency shifts in normal-hearing participants and then use this range to determine

abnormal tip frequency shifts. Sęk et al. (2005) proposed that abnormal tip frequency

shifts are an indication of substantial cochlear damage Tip frequency shifts were

expected to be in the normal range when participants with hearing impairment have at

least partial cochlear function at a given probe frequency.

High-frequency hearing loss is the most common type of hearing loss seen in individuals after chemotherapy. Substantial cochlear damage at high frequencies results in tip frequency shifts to lower frequencies. Therefore, determining the lower

minimum would establish a tip frequency boundary. If participants had tip frequencies which were lower in frequency than the boundary, substantial cochlear damage is likely.

In the adult population, using estimates provided by the Quadratic Function

method, two standard deviations below the average results in a maximum tip frequency

shift of -0.6% at 500 Hz (495 Hz), -3.4% at 1000 Hz (965 Hz), -4.4% at 2000 Hz (1910 Hz)

and -10% at 4000 Hz (3600 Hz). However, it may be simpler as a clinical tool (and to

minimize false positive results) to use the largest downward shift for any frequency,

here a 10% downward shift (450 Hz, 900 Hz, 1800 Hz and 3600 Hz) in the adult

population. In the adult population, no normal-hearing participant produced tip

frequency estimates more than 10% below the probe frequency.

In the pediatric data, the large variability across conditions makes it unlikely that

a 10% tip frequency shift would be appropriate. Using the Quadratic Function, two

standard deviations below the average results in a maximum tip frequency shifts of

-8.02% at 500 Hz (460 Hz), -9.85% at 1000 Hz (901 Hz), -6.58% at 2000 Hz (1868 Hz) and

-11.36% at 4000 Hz (3545 Hz). Thus, a 11.5% downward tip frequency shift would

encompass the largest downward tip shift across all frequencies. However, many children with normal hearing had downward tip shifts greater than 12% with some more than 17%. This made establishing a normal range of downward tip shift difficult in children. This issue will be reviewed further in the discussion section.

Table 8: Number of PTC pairs, average error difference and standard deviation between PTC pairs for each tip frequency estimation method at each frequency in children.

500 Hz 1000 Hz 2000 Hz 4000 Hz

Double Linear Reg N=13 N=18 N=19 N=14 Average 4.5% 7.7% 3.0% 8.2% SD 4.2% 6.1% 3.2% 6.0% 2 Point Moving Average N=16 N=21 N=21 N=17 Average 7.1% 7.0% 3.8% 6.0% SD 4.6% 5.8% 2.6% 4.8% 4 Point Moving Average N=16 N=21 N=21 N=17 Average 7.1% 7.0% 3.8% 6.0% SD 4.6% 5.8% 2.6% 4.8% Quadratic Function N=14 N=20 N=21 N=14 Average 5.1% 7.2% 3.5% 6.5% SD 7.2% 5.8% 3.9% 6.9% Double Low-Pass .25 N=16 N=20 N=21 N=17 Average 5.9% 7.8% 5.6% 5.9% SD 5.1% 5.8% 8.0% 5.0% Double Low-Pass .20 N=16 N=21 N=21 N=17 Average 6.5% 8.6% 6.1% 6.2% SD 4.5% 6.0% 8.3% 5.6% Double Low-Pass .15 N=16 N=21 N=21 N=17 Average 7.5% 11.3% 5.9% 10.8% SD 5.5% 11.5% 8.4% 13.7% RoEx N=8 N=14 N=17 N=7 Average 6.4% 8.2% 3.9% 5.8% SD 6.1% 7.3% 3.6% 4.7%

4.2: Participants with Hearing Impairment

4.2.1: Speech Perception

Recall that the hearing aid was programmed to match a DSL 5.0 child prescription and each participant’s hearing aid setting was verified via Speechmapping in the Verifit2 test box. Verification allowed confirmation that the hearing aid was programmed appropriately for each participant and provided a visual and numerical representation of the audibility of the recorded speech stimuli.

For each participant, the audibility of the recorded speech stimuli can be discussed in two ways. First, the full audibility cut-off is the highest frequency where full access to the LTSS is provided. Here, the lowest intensities of the LTSS (as determined by the bottom line on the Verifit graph for the 65 dB SPL speech stimuli) fall at least 5 dB

SPL above threshold. Second, the partial audibility cut-off is the highest frequency where the average of the LTSS is at least 5 dB SPL above threshold. Between the full and partial audibility frequency cut-offs, less-intense speech sounds within this frequency range may fall below the participant’s threshold and would not be audible.

Given the sloping nature of a participant’s hearing loss, this range of partial audibility may cover a significant portion of the speech spectrum. Table 9 provides audibility information for each participant with hearing impairment, including ear(s) tested, and the full and partial audibility frequency cut-offs. Appendix E provides the Verifit2

Speechmapping results and speech perception performance for each participant with hearing impairment.

Table 9: Ear(s) tested and full and partial audibility cut-off frequencies for participants with hearing impairment.

Ear Full Audibility Partial Audibility

Adult 1 L 6000 8000

Adult 2 L 6000 8000

Adult 3 L 6000 7000

Adult 4 L 1000 2000

R 4000 6000

Adult 5 L 1000 4000

R 1000 4000

Child 1 R 3000 4000

Child 2 L 6000 8000

Child 3 R 6000 7000

Child 4 L 4000 6000

Child 5 R 4000 6000

Figure 9 presents speech perception data for the adults with hearing impairment

as compared to the average (± 1 standard deviation) normal-hearing adult participant

data across SNR conditions. Figure 10 presents the speech perception data for the

children with hearing impairment as compared to the average (± 1 standard deviation)

normal-hearing child participant data across SNR conditions. Individual participant

performance is presented as different colored lines with the same colors representing

the same participants across SNR conditions. For all figures, the normal hearing

averages are presented in black with corresponding symbols.

All participants tended to have improved speech perception performance with improved SNR conditions. However, in the -3 dB SNR condition, many participants were at floor performance, even up to a filter cut-off frequency of 4000 Hz.

As filter cut-off frequency increased, speech perception performance varied widely between adult and child participants, even when audibility was accounted for.

Generally, when full audibility of the speech frequency range was provided, speech perception performance increased with increasing low-pass cut-off frequency. This trend continues when partial access (the average LTSS is at least 5 dB SPL above threshold) was available. When low-pass filter cut-off frequency increased into ranges

where aided gain did not provide full (or partial) audibility, speech perception

performance reflected this. In most conditions where this occurred, speech perception

performance remained stable. Of note, one child participant (#1) performed more

poorly when additional high-frequency information was provided, particularly between

4000 and 6000 Hz in the +3 and 0 dB SNR conditions. Alternately, adult participant #5 had a notable difference in speech perception performance between ears but continued to improve as additional high-frequency information was provided, even when no additional audibility was provided.

verage (± 1 (± verage 3 dB SNR, 0 SNR, +3 SNR. SNR, 0 SNR, dB 3 From left: - left: From . hearing adult participant data participant adult hearing - Impaired adult participant speech perception data as compared to the a the to compared as data perception speech participant adult Impaired - Hearing

Figure 9: normal deviation) standard

3 SNR, 0 SNR, +3 SNR. +3 0 SNR, 3 - hearing child participant data. From left: From data. participant child hearing - Impaired child participant speech perception data as compared to the average (± 1 1 (± average the to compared as data perception speech participant child Impaired - Hearing

Figure 10: Figure normal deviation) standard

4.2.2: Threshold Equalizing Noise Test

Current published protocols using the TEN test suggest completing only the test

frequencies most likely to fall into ranges of substantial cochlear damage. However, in

this study, masked thresholds were obtained at additional frequencies (typically 500 and

1000 Hz) when the participant was able to complete the task without fatigue in order to

obtain additional masked threshold information from this population. Tolerance was an

issue for child participant #4 when lower frequencies were attempted, thus lower

frequency masked thresholds were not obtained for this participant.

Completing the TEN test at both low and high frequencies provided masked

thresholds for regions of “clinically” normal-hearing (thresholds at or better than 20 dB

HL) and regions of hearing loss for the same participant. Comparison between high- and low- frequency regions can identify if a participant has globally elevated masked thresholds or if masked thresholds are abnormally high for specific frequencies only.

TEN test masked threshold results at each frequency for the adults and children with hearing impairment are presented in Figure 11 and 12 respectively. The color coding and shading for each participant remains consistent throughout and are as noted in Figure 11. Masked thresholds were obtained at the same levels (30, 50, and 70 dB

HL) as normal-hearing control participants when appropriate. For all participants

(except as previously noted for child participant #4), a missing data point indicates that

the participant’s unmasked pure tone threshold exceeded the TEN presentation level.

At higher thresholds, masked thresholds were obtained for intensities at or 10 dB above

unmasked thresholds to provide appropriate masking. Inconclusive test results were

noted when unmasked pure tone thresholds exceeded 80 dB HL due to established

intensity limits. Inter-octave frequencies were tested when thresholds at higher octave

frequencies were inconclusive due to either high unmasked pure tone thresholds or

loudness tolerance issues. As an example, 1500 Hz was tested for adult participant #4

because results were inconclusive due to thresholds above 80 dB HL at 2000, 3000 &

4000 Hz in the left ear. This participant did not have abnormally high masked threshold results at 1500 Hz in the left ear.

Two participants met the criteria for substantial cochlear damage with masked thresholds more than 10 dB above TEN presentation level and 10 dB or more above

unmasked threshold. Abnormally high masked thresholds are marked in Figures 15 and

16 with an asterisk (*). Hearing-impaired adult participant #5 had abnormally high

masked thresholds, between 12 and 18 dB above TEN presentation level, at 3000 and

4000 Hz in both ears. Hearing-impaired child participant #1 had an abnormally high

masked threshold of 12 dB above TEN presentation level at 4000 Hz in the right ear

only.

00 Hz 4000 Hz 15

lds for the adults with hearing impairment using the TEN TEN the using impairment hearing with adults the for lds 000 Hz 000 Hz 3 1 Individual masked thresho masked Individual

est with average adult mean (+2 SD). An asterisk (*) indicates abnormally high masked masked high abnormally indicates (*) asterisk An SD). mean (+2 adult average with est Figure 11: 11: Figure t threshold.

00 Hz 000 5 2

2000 Hz

000 Hz 1 4000 Hz Individual masked thresholds for the children with hearing impairment using the the using impairment hearing with children the for thresholds masked Individual

Figure 12: 12: Figure masked high abnormally indicates (*) asterisk An SD). (+2 mean child average with test TEN threshold.

00 Hz 5 3000 Hz

4.2.3: Psychophysical Tuning Curves

As with the TEN test, published research suggests beginning PTC collection at frequencies believed to be within regions of substantial cochlear damage. Thus, the frequencies of 1500 and 3000 Hz were added to 500 Hz, 10000 Hz, 2000 Hz and 4000 Hz in participants with hearing impairment. Fast PTCs were attempted at frequencies for which the unmasked threshold was less than 80 dB HL. Fast PTCs were initially tested in regions of hearing loss where potential tip shift was most likely. Additional PTCs were attempted, including frequencies of clinically normal hearing, if participant concentration permitted.

All participants with hearing impairment were able to complete at least one Fast

PTC; however, notable differences between participants were seen. All adult

participants with hearing impairment provided acceptable PTCs comparable to normal-

hearing control participants in the lower frequencies (500 and 1000 Hz), where hearing

thresholds were within or close to normal-hearing limits. However, three of five adult

participants had difficulty providing acceptable PTCs at higher frequencies. The ability

to provide acceptable PTCs in the high frequencies was not related to hearing loss, as

some participants with relatively lesser degrees of hearing loss did not provide

acceptable tuning curves while participants with greater hearing loss did. When adult

participants were able to complete the task and produce an acceptable PTC, most were able to complete two PTCs at a given frequency (71% of times attempted).

In children, the completion rates were poorer across all frequencies attempted, regardless of hearing threshold at a given frequency. All children were able to complete at least one acceptable PTC at 2000 Hz. Hearing-impaired children were unable to produce any acceptable tuning curves at 4000 Hz (all children attempted) and one child was unable to complete 1000 Hz (single attempt). However, only one participant was able to complete two acceptable PTCs at a given frequency. This did not appear to be related to age, as even the oldest participant was only able to produce a single acceptable PTC.

The tip frequency estimates provided by the five methods in the Fast PTC software were examined for the participants with hearing impairment. Table 10 lists the number of acceptable tuning curves obtained from both adults and children with hearing impairment at each frequency and the number of times the method produced an actual value. Similarities in tip frequency estimates provided by the different methods were seen between the participants with normal hearing and those with hearing impairment. As was seen in normal-hearing control participants, all but three methods provided estimates 100% of the time, with the Quadratic Function providing estimates 89% of the time, the Double linear regression 72% and the RoEx 23%.

Table 10: Acceptable tuning curves and method success rate for adult and children with hearing impairment.

500 Hz 1000 HZ 1500 HZ 2000 Hz 2000 Hz 3000 Hz 3000 Hz 4000 Hz

Adults Adults Adults Adults Children Adults Children Adults

N=11 N=12 N=2 N=7 N=6 N=2 N=2 N=4

Double Linear 7 11 1 4 5 0 2 3 Regression 2pt Moving 11 12 2 7 6 2 2 4 Average 4pt Moving 11 12 2 7 6 2 2 4 Average Quadratic 11 12 2 6 6 0 2 2 Function Double Low- 11 12 2 7 6 2 2 4 Pass 0.25 Double Low- 11 12 2 7 6 2 2 4 Pass 0.20 Double Low- 11 12 2 7 6 2 2 4 Pass 0.15 RoEx 2 3 2 1 6 0 0 1

Table 11 lists the mean, standard deviation and minimum tip frequency error for each method at each frequency for participants with hearing impairment. The percent error for each PTC was determined as in the normal-hearing participant analysis. Due to

the limited number of PTCs obtained in children, the child and adult data for 2000 and

3000 Hz data were combined. As was seen in the normal-hearing control participants,

the Quadratic Function again provided the lowest average error (0.55%) with the double

linear regression and RoEx methods having the highest error. Standard deviations and

both minimum and maximum values were comparable to normal-hearing participant

data. This supports the use of the Quadratic Function method for tip frequency

estimation for both children and adults with normal hearing loss due to chemotherapy.

In the normal-hearing PTC analysis, a downward tip-frequency shift of greater than 10% in adults and greater than 12% in children was proposed as abnormal for the determination of regions of substantial cochlear damage. Applying the same rule to participants with hearing impairment, two standard deviations below the average, results in a maximum tip frequency error of -4.04% at 500 Hz (480 Hz), -8.66% at 1000

Hz (991 Hz), -8.71% at 1500 Hz (1370 Hz), -4.65% at 2000 Hz (1907 Hz), -1.1% at 3000 Hz

(2997 Hz) and 2.45% at 4000 Hz (3902 Hz). Results from participants with hearing impairment also supports the use of a 10% tip frequency shift in adults. In this study, no participants with hearing impairment had tip frequency estimates that fell outside of this range. This would indicate that where PTCs could be obtained, no participant with hearing impairment had a region of substantial cochlear damage.

The Quadratic Function was identified as the most effective tip-frequency estimation method and a shift of greater than 10% was identified as an abnormally large tip shift in adults with normal hearing and those with hearing impairment. However,

the inability of adults with hearing impairment to provide acceptable high-frequency

PTCs as compared to low-frequency PTCs, is concerning, because high frequencies are of the greatest interest in this population. In addition, children with hearing impairment were generally unable to provide acceptable tuning curves across all frequencies tested, which limits the application of Fast PTCs in this population. These concerns will be further explored in the Discussion.

Table 11: Mean, standard deviation, and minimum tip frequency error for each method is presented by frequency for participants with hearing impairment.

500 1000 1500 2000 3000 4000 Average Double Linear Regression Average 5.94% 5.45% 7.27% 6.91% 2.37% 11.00% 6.49% SD 2.59% 3.08% CNE 1.73% 6.88% 2.08% 3.76% Min 2.40% 1.80% 7.27% 4.95% -2.50% 8.60% -2.50% 2 Point Moving Average Average 4.89% 2.84% 2.93% 3.09% 0.53% 3.64% 2.99% SD 5.80% 4.89% 2.83% 4.50% 2.06% 4.94% 4.37% Min -1.40% -5.20% 0.93% -4.50% -1.50% -1.98% -5.20% 4 Point Moving Average Average 6.00% 2.20% 2.57% 5.13% 0.71% 2.49% 3.18% SD 5.82% 5.65% 1.84% 4.14% 1.72% 5.12% 4.39% Min -0.60% -8.80% 1.27% -2.05% -0.87% -2.53% -8.80% Quadratic Function Average 3.18% -0.58% -8.43% 2.99% 1.02% 5.11% 0.55% SD 3.61% 4.04% 0.14% 3.82% 1.06% 1.33% 2.80% Min -1.80% -5.80% -8.53% -2.15% 0.27% 4.18% -8.53% Double Low-Pass 0.25 Average 6.18% 3.58% 4.50% 5.08% 0.05% 4.39% 3.97% SD 6.10% 4.30% 2.40% 4.79% 4.69% 5.57% 4.79% Min 0.00% -0.90% 2.80% -1.10% -6.23% -1.73% -6.23% Double Low-Pass 0.20 Average 5.95% 2.50% 6.67% 4.95% -1.55% 5.14% 3.94% SD 4.22% 4.87% 0.66% 4.12% 7.99% 5.51% 5.05% Min 0.60% -3.20% 6.20% 0.70% -8.97% -2.23% -8.97% Double Low-Pass 0.15 Average 1.42% -0.89% 2.27% 3.12% 0.61% 4.06% 1.76% SD 5.80% 5.59% 4.53% 5.48% 9.21% 6.29% 6.32% Min -13.80% -14.40% -0.93% -7.40% -12.20% -3.78% -14.40% RoEx Average 3.30% 5.33% -0.83% 8.66% CNE 6.60% 4.61% SD 0.14% 4.02% 9.29% 6.31% CNE CNE 5.96% Min 3.20% 2.00% -7.40% 1.95% CNE 6.60% -7.40%

Chapter 5: Discussion

5.1: Speech Perception

One purpose of the current study was to investigate the speech perception

abilities of both adults and children with hearing loss due to chemotherapy. This was

accomplished by presenting recorded sentences under different SNR and low-pass filter conditions. The primary finding from this study was that children and adults with hearing loss due to chemotherapy have poorer speech perception than the average speech perception of normal hearing controls.

As expected, improving the SNR from -3 dB to 0 dB to +3 dB resulted in improved speech perception for the normal-hearing control groups (children and adults). This finding is unsurprising, as it has been well-established that speech perception is better in lower levels of background noise (McCreery & Stelmachowicz,

2011; Silberer et al., 2015). Similarly, as more of the signal was presented with increasing available high-frequency cues (i.e., higher low-pass filter cut-off frequencies),

speech perception for the normal-hearing control groups also improved. Again, this

finding is consistent with previous work demonstrating the importance of high-

frequency audibility for speech perception (Pittman et al., 2005; Stelmachowicz et al.,

2000)

In a small subset of low-frequency filter cut-off conditions, the child and adult

participants with hearing impairment performed within the normal range (e.g., within

two standard deviations of average normal performance). Specifically, speech

perception performance was like that of the normal-hearing controls at the lowest filter

cut-off frequencies and the poorest SNR conditions (see Figures 9 and 10). The poor

speech perception performance of normal hearing subjects at the lowest filter cut-off

frequencies is likely a primary reason for this. Speech perception performance within

the normal range may be also due to the participants with hearing impairment having

normal hearing and full audibility within the low-frequency range. Generally, as the

filter cut-off frequency increased, the speech perception performance for the adults

with hearing loss were more likely to fall outside the normal range (i.e., poorer than two

standard deviations of average normal performance). Performance outside of the

normal range is likely related to greater degrees of hearing loss and, therefore, limited

access to high- frequency speech stimuli via amplification for these adults. An

interesting point is that while speech perception performance increased with improved

SNR, speech perception performance for adults with hearing impairment trended outside of the normal range as SNR improved. This suggests that while participants with hearing impairment were able to capitalize on the improved SNR, those participants

were not able to make as great a use of the improvement in SNR as adults with normal

hearing. This lack of improvement in performance with increasing SNR was not directly

linked to degree of hearing loss. For example, hearing-impaired adult participant #1 had

the mildest degree of hearing loss yet had notably poorer speech perception

performance compared to both adult controls and most of the other adults with hearing

impairment, even in the best SNR conditions. Although outside the scope of the current

study, poorer-than-expected speech perception performance may be related to the neurocognitive side effects of chemotherapy. Research has shown that participants

receiving platinum chemotherapies may have verbal memory deficits and declines in

informational processing abilities following treatment (Castellon et al., 2004) as well as

declines in working memory (Mulhern & Palmer, 2003), all of which would be expected

in negatively impact speech perception. In addition, neurological damage due to

chemotherapy may include central auditory pathway compromise, further impacting

speech perception abilities (Einarsson et al., 2011). Additional treatment factors such as

radiation may also can also damage the central nervous system, resulting in participants

exhibiting greater difficulty understanding speech in noise than would be expected

given pure tone thresholds (Gurney et al., 2009). Future research investigating speech perception in participants with hearing loss due to chemotherapy would therefor

benefit from inclusion of a cognitive assessment.

Speech perception performance for children with hearing impairment generally

improved with increasing SNR and filter cut-off frequency. Although speech perception

performance for the children with hearing loss fell within two standard deviations of

normal, speech perception performance was generally poorer than the average performance of children with normal hearing. Four of five children with hearing impairment had speech perception scores that fell more than one standard deviation below the normal range for at least one condition. Two potential reasons for the similarity in performance between the children with normal hearing and those with hearing loss includes the floor performance (near 0%) at the low cut-off frequencies for both groups of children, as well as the high degree of variability seen in the children with normal-hearing. Large variability in speech perception performance is commonly seen in pediatric research making it difficult to observe meaningful differences between groups (McCreery & Stelmachowicz, 2011; Scollie, 2008).

Generally, children and adults with hearing loss demonstrated improved speech perception performance as the low-pass filter frequency is increased (i.e., provision of additional high-frequency audibility). The finding of improved speech perception performance with increasing high-frequency audibility agrees with previously published research. Hornsby et al. (2011) found that while speech perception performance varied significantly among participants, most participants with high-frequency hearing loss had improved speech perception with increasing high-frequency acoustic cues. Cox et al.

(2012) found that while participants both with and without diagnosed cochlear dead

regions generally had improved speech perception performance with increasing high- frequency audibility, participants with cochlear dead regions did not show the same level of improvement as high-frequency audibility increased. An important consideration in the current research is that most participants with hearing loss were provided with full audibility of the average LTSS through 4000 to 6000 Hz and partial audibility through 6000 to 8000 Hz by presenting the speech signal through hearing aids.

Thus, most children and adults with hearing loss were able to utilize high-frequency audibility for improved speech perception to some extent. An interesting finding of the current study is that many participants with hearing impairment had small but notable improvements speech perception performance when even a small part of the frequency range became audible. For example, adult participant #4 and child participant #5 continued to show improvement between the 6000 and 8000 Hz cut-off frequencies even with no audibility provided at 8000 Hz. This is likely due to partial audibility of the speech spectrum between 6000 and 7000 Hz contributing to speech perception.

Most participants with hearing impairment exhibited improved speech perception as the low-pass filter frequency increased; however, there were two notable exceptions. Hearing-impaired child #1 was the only participant with hearing loss who consistently had poorer speech perception score at higher cut-off frequencies than at lower cut-off frequencies. For this participant with hearing impairment, increasing high-

frequency audibility not only failed to improve speech perception, but also at a certain point, caused performance to decrease. Adult participant #5 was the second participant who did not have substantial gains in speech perception as low-pass filter frequency

increased and whose speech perception performance was slightly poorer in the highest filter conditions as compared to the lower filter conditions. The speech perception results of the these two participants with hearing loss due to chemotherapy support research suggesting individuals with abnormal cochlear function exhibit reduced speech perception as high-frequency audibility is provided (Baer et al., 2002; Vickers et al.,

2001).

5.2: Assessment of Cochlear Function

One method of evaluating abnormal cochlear function is via psychoacoustic measures such as the TEN test and Fast PTCs. Thus, the second purpose of the current study was the evaluation of cochlear function in participants with hearing loss due to chemotherapy using the TEN test and Fast PTC procedure.

The average masked thresholds for adults and children with normal hearing were within ± 2 dB of the TEN presentation level across all frequencies and intensity levels. This supports the development and purpose of the TEN noise as discussed in

Moore et al. (2004) as masked thresholds were raised to the intensity level (in dB HL) of

the TEN noise. There was a significant difference between average masked thresholds in adults and children, however the difference at all frequencies was less than a single

step size (here 2 dB). Thus, while statistically significant, differences within a single step

size are not clinically significant.

Results for the TEN test were considered abnormal if masked thresholds fell more than two standard deviations above the mean of the normal-hearing child and adult group values. For both children and adults, masked thresholds were deemed abnormally high if more than 6 dB above the TEN noise presentation level. A 6 dB elevated masked threshold is smaller than published data, particularly in pediatric participants. A smaller range of normal for masked thresholds would result in a larger number of positive TEN results and a larger number of participants identified with substantial cochlear damage. Previous results suggest that masked thresholds 10 dB above TEN level in adults and 15 dB above TEN level in children are indicative of abnormal cochlear function (Malicka et al., 2010, Moore et al., 2004).

One concern when using masking tasks such as the TEN test with participants with hearing impairment is that some individuals with hearing impairment experience a greater effect of masking as compared to individuals with normal hearing (Moore et al.,

2000). When unmasked hearing thresholds were no greater than a moderate hearing loss, masked thresholds for participants with hearing impairment were like normal-

hearing control participants. Thus, globally elevated thresholds were not seen in any

participant with hearing impairment.

The tip frequency estimates results from the adults with normal hearing using

Fast PTCs are consistent with published data and show minimal tip shift (Sęk & Moore,

2011). This is to be expected, as participants with normal hearing should exhibit normal cochlear function when assessed via Fast PTCs. Evaluation of the tip frequency estimates reveals that the Quadratic Function method was the most effective method as it yielded the lowest average tip shift and error measurements across all participants with normal hearing and adults with hearing impairment. This is consistent with previously published data suggesting that the Quadratic Function method yielded the smallest tip shift values (i.e., deviation from probe frequency) (Myers & Malicka, 2014;

Sęk & Moore, 2011). Results from adults with normal hearing revealed that tip shifts of

10% or less at a given frequency are within the normal range and no adult with normal hearing produced a PTC with a tip frequency estimate that was more than 10% below the stimulus frequency. Because the participants with hearing impairment have high- frequency hearing loss, abnormal tip frequency shifts to frequencies below the probe tone are expected when abnormal cochlear function is present, thus only downward tip shifts (i.e., tip frequencies that are lower frequency than the probe tone) are considered abnormal. This is consistent with published research (Sęk et al., 2007).

100

Results from the child population are more variable than the adult data and suggest that a tip shift of greater than 12% would be abnormal. Larger variability and

larger average tip shift has been seen in previously published research, with researchers

suggesting normal tips shifts as much as 20% of the probe frequency (Malicka et al.,

2009, 2010). Data from the present study do not support a 20% tip shift; as such, a large

range would potentially limit the ability of the test to identify abnormal results.

However, while a 12% tip shift is greater than two standard deviations from the normal-

hearing child average, one child with normal hearing in this study had downward tip shifts greater than 12%, thus suggesting the potential for false positive results when using a 12% criterion. To limit false positive results, tip shifts greater than 15% may be considered as abnormal in children while still being conservative enough not to miss potential abnormal results in children with hearing impairment.

The results of the TEN test and Fast PTCs in participants with hearing impairment

reveal two key findings regarding cochlear function in this population. First, when

participants with hearing impairment have pure tone thresholds within the normal

hearing range, measures of cochlear function across both the TEN test and Fast PTCs were consistent with normal-hearing control participants. Specifically, masked thresholds obtained via the TEN test were not elevated above 6 dB. In addition, no Fast

PTC tip frequency shift of more than 10% in adults with hearing impairment or more than 12% in children with hearing impairment was seen. Thus, participants with hearing

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impairment had essentially normal measures of cochlear function in regions of normal to near normal hearing. Results indicate normal cochlear function, supporting previous research indicating that the majority of cochlear damage due to platinum-based chemotherapy is concentrated in the high-frequencies (Knight et al., 2007).

The second notable finding is that results from the measures of cochlear function varied when high-frequency regions were assessed, even when pure tone thresholds were in the mild hearing loss range. Masked thresholds obtained via the TEN test were not elevated for most participants with hearing impairment when assessed in the high frequencies (between 2000 and 4000 Hz). Thus, TEN test results suggest that most participants with hearing impairment did not have abnormal cochlear function between 2000 and 4000 Hz. However, abnormally high masked thresholds were evident for adult participant #5 and child participant #1, who both had masked thresholds greater than 10 dB above TEN level and greater than 10 dB above the unmasked threshold. Therefore, under both the current study criteria of 6 dB and published research criteria of 10 dB, TEN results from these two participants indicate regions of abnormal cochlear function in at least one ear.

In contrast, the Fast PTCs provided little to no additional information on the cochlear function of participants with hearing impairment above approximately 2000

Hz, due primarily to the participants’ inability to complete the task at high frequencies.

Although higher intensity levels and tolerance issues could have been a concern for

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severe hearing losses, three out of five adults with hearing impairment had difficulty

with high frequency PTCs even when pure tone thresholds were in the mild to moderate hearing loss range. In children with hearing impairment, the most significant concern

was the inability to complete the task, regardless of frequency. This did not appear to

be directly age–related, as the oldest child participant was only able to produce a single

acceptable PTC. Nor did it appear to be related to hearing loss, as children were unable

to complete the task even at relatively lower frequencies where hearing thresholds

were normal. Thus, participants had difficulty with the task even when assessing regions

of less cochlear damage. This issue was not seen (or at least not noted) in other

published research (Pepler et al., 2014; Sęk, & Moore, 2011). The two adult participants

with the most severe high-frequency hearing losses were unable to produce a single

acceptable tuning curve at the highest frequencies.

A potential reason for a participant’s inability to complete the Fast PTC task in

the high frequencies may be chemotherapy exposure. Frequency selectivity in participants with hearing loss due to chemotherapy has not been investigated previously, thus a comparison population is unavailable. However, the specific pattern

of cochlear damage due to platinum chemotherapies may have affected the selectivity

of higher frequencies in such a way that the Fast PTC procedure is impacted. A PTC

judged as “unacceptable” according to the current criteria, such as large runs between

reversals or flat tracings, may in fact represent the true pattern of cochlear function in

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participants with hearing loss due to chemotherapy. Given that children were generally unable to complete the task at any frequency, a second factor specific to children in the current study may be attributed to reduced attention and neurocognitive delays.

Published research had explored the significant adverse effects of chemotherapy

(Gurney et al., 2009; Schreiber et al., 2014). Reduced attention and neurocognitive delays may have affected the participant’s ability to complete the task, either due to the time required to complete the task or due to the cognitive requirements of the task itself. In either case, results from the current study suggests Fast PTCs (as implemented here) provide minimal interpretable data for high-frequency regions when evaluated in participants with hearing loss due to chemotherapy.

5.3: Special Cases in Participants with Hearing Impairment

One purpose of the current study was to determine if participants with abnormal speech perception results also had abnormal measures of cochlear function.

Specifically, this study sought to determine if abnormal cochlear function (as evaluated by the TEN test and Fast PTCs) measures correlated with poorer speech perception performance as high-frequency audibility was provided. Most of the participants with hearing impairment exhibited speech perception performance that, although poorer than normal-hearing control participants, improved as SNR and filter settings improved.

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Similarly, the same majority of participants with hearing impairment also demonstrated normal masked thresholds on the TEN test. For this set of participants, the PTC data suggested normal cochlear function in the low frequencies where pure tone thresholds were in the normal range. However, PTCs in high frequencies revealed difficulty with task completion and therefore, minimally interpretable data. The results support the provision of high-frequency audibility (via amplification) for most individuals with hearing loss due to chemotherapy. In contrast, a small number of participants with hearing impairment had abnormal results on measures of cochlear function (e.g. abnormally high masked thresholds on the TEN test) and/or speech perception performance that did not follow the typical pattern of improvement as SNR and filter cut-off improved. Because the results can have implications in the provision of high- frequency audibility, these participants are discussed below. Note that pure tone audiograms for individual participants can be found in Figures 1 and 2, participant demographics including treatment variables can be found in Table 1 and audibility information can be found in Table 9.

5.3.1: Hearing-Impaired Adult Participant #1

Adult participant #1 was a 49-year-old female with a history of tonsil cancer who received cisplatin chemotherapy and underwent radiation of the left side of her throat.

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Her pure-tone hearing was normal through 4000 Hz, sloping to a mild loss at 8000 Hz.

The left ear of this participant was selected for speech perception testing due to the slightly poorer thresholds. Audibility of the speech stimuli was provided via amplification and this participant had full audibility of the speech stimuli past 6000 Hz and partial audibility through 8000 Hz.

Although hearing thresholds were in the normal range through 4000 Hz, speech perception performance was outside of the normal range in all three SNR conditions. As the SNR improved, the number of filter cut-off conditions in which performance fell out of the normal range increased so that by the +3 dB SNR condition, speech perception performance fell outside of the normal range across all filter cut-off frequency conditions. This means that adult participant #1 had substantial difficulty with the speech perception task overall and was unable to make notable gains in speech perception as the SNR improved.

Masked TEN thresholds for adult participant #1 were within the normal range for all frequencies and at all intensity levels. This participant was also able to complete the

Fast PTC task for all four frequencies with tip frequency estimates within the normal range. Normal TEN test and Fast PTC results suggest that substantial cochlear damage may not be the contributing factor to this participant’s speech perception difficulties.

The negative impact of radiation on central processes such as verbal memory and processing abilities has previously been documented (Castellon et al., 2004) and

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was likely a contributing cause of her speech perception difficulties. Although not within the scope of this study, the impact of radiation on speech perception is an important consideration for future research.

5.3.2: Hearing-Impaired Adult Participant #4

Adult participant #4 was a 52-year-old male with a history of medulloblastoma who received cisplatin chemotherapy and radiation on the left side of his brain. He had a significant asymmetry in his hearing following treatment. Hearing thresholds in the right ear were normal through 2000 Hz sloping to a severe loss at 8000 Hz. Hearing thresholds in the left ear were normal through 1000 Hz steeply sloping to a severe-to- profound loss from 1500 to 8000 Hz. Because of the asymmetry, both ears of this participant were tested. With amplification, full audibility was provided through 1000 Hz in the left ear and 4000 Hz in the right ear, and partial audibility was provided through

2000 Hz in the left ear and through 6000 Hz in the right ear.

Speech perception performance in the left ear was notably below the normal range for multiple filter cut-off frequencies across all SNR conditions. Speech perception performance generally improved as filter cut-off frequency increased and

SNR improved when full or partial audibility was provided. Speech perception performance remained poor but did not decrease in filter cut-off conditions where no

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additional high-frequency audibility was provided. Speech perception performance was notably better for the right ear than the left ear across all conditions, even when similar levels of audibility were provided. While better speech perception performance in the right ear can generally be attributed to better hearing thresholds and subsequent available audibility, the impact of radiation on the left, both on hearing thresholds and speech perception must be considered. It should also be noted that the right ear was tested second, and thus improvements due to learning effects cannot be ruled out.

TEN test results in the lower frequencies for the left ear (500 to 1500 Hz) and at

all frequencies in the right ear were not elevated, suggesting against significant cochlear

damage within this range. This participant was the only participant to have inconclusive

results on the TEN test due to the severity of the hearing loss in the left ear.

Inconclusive results can occur when thresholds are above 75 dB HL, as the high TEN

noise intensity levels required to effectively mask the pure tone often cannot be

achieved due to tolerance issues. Summers et al. (2003) discussed inconclusive results, noting that the degree of hearing loss that yields inconclusive results are typically so severe that substantial cochlear damage is likely. In this participant, high-frequency

hearing loss in the left ear was in the severe to profound range and was the side of radiation therapy, supporting the likelihood of substantial cochlear damage due to both

chemotherapy and radiation.

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Fast PTC results for the left ear revealed normal tuning curves at 500 and 1000

Hz, but a failure to complete an acceptable tuning curve at 1500 Hz. The tuning curve at

1500 Hz had an abnormal shape with a steep slope initially downward, suggesting that the participant did not hear the probe once the noise began until the noise level was far below the level of the probe tone (Figure 13). For the flattened portion of the recording, the intensity level of the masker was far below the intensity of the probe tone, yet the participant responded as if the probe tone was intermittently audible.

Thus, it is possible the participant was responding to a different auditory signal other than the actual probe tone at this frequency. The participant reported that he heard a pulsed sound throughout the entire test, but at a certain point the sound changed and

“moved” in pitch. This participant may have been unintentionally responding to the masker or potentially to low-frequency combination tones (Kluk & Moore, 2004, 2005).

Fast PTCs for the right ear were normal from 500 to 3000 Hz, but flat at 4000 Hz (Figure

14).

The ability to complete the Fast PTC task at lower frequencies, but not in regions of hearing loss may in fact be the indication that a change in cochlear function occurred rather than a total inability to complete high-frequency tuning curves. Given the configuration and degree of pure tone thresholds, a change in cochlear function in the higher frequencies is unsurprising and assumptions about cochlear status can be made based on the audiogram. However, this did not address the purpose of the study. The

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intent of the tests was to investigate the potential for abnormal cochlear function, and,

with this participant, both the TEN test and Fast PTCs fall short, as cochlear status could not be determined.

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Figure 13: Fast PTC raw data results for a 1500 Hz probe tone for the left ear of Hearing-Impaired Adult Participant #4

Figure 14: Fast PTC raw data results for a 4000 Hz probe tone for the right ear of Hearing-Impaired Adult P articipant #4

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5.3.3: Hearing-Impaired Adult Participant #5

Adult participant #5 was a 61-year-old male with a history of throat cancer who

received cisplatin chemotherapy and radiation on the right side of his throat. Hearing

thresholds were normal through 1000 Hz sloping to a severe to profound loss from 3000

to 8000 Hz. There was an asymmetry in hearing loss at 1500 Hz only with the right ear

being poorer. Both ears of this participant were tested due to the unilateral radiation.

Audibility provided by the hearing aid was similar between ears with full audibility

through 1000 Hz and partial audibility through 4000 Hz.

Speech perception performance in both ears was below the normal range for the

4000, 6000 and 8000 Hz filter cut frequency conditions for all SNR conditions. Although

speech perception performance was below normal across conditions and speech perception in both ears was 0% for the 1000 Hz filter cut-off condition, speech

perception performance in the left ear improved at a much different rate as compared

to the right. Speech perception performance in the left ear steadily improved as filter

cut-off frequency increased. This same pattern of improvement was not seen in the

right ear as speech perception performance essentially plateaued by the 4000 Hz filter cut-off condition.

Adult participant #5 was the only adult participant to have abnormally high

masked thresholds on the TEN test. TEN results were within the normal range 500 to

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2000 Hz but were 12 dB above TEN presentation level at 3000 and 4000 Hz in both ears.

High masked thresholds on the TEN test suggest grossly abnormal cochlear function and

the potential for a cochlear dead region in that frequency range. For this participant,

TEN results suggest grossly abnormal cochlear function at least between 3000 and 4000

Hz. It is likely that cochlear function continued to be grossly abnormal above 4000 Hz,

however the TEN HL test does not evaluate cochlear function above 4000 Hz. Fast PTC results were normal at 500 and 1000 Hz in both ears. At 1500 Hz, PTCs were essentially flat in both ears. Due to the severity of the loss, PTCs could not be completed at 2000

Hz or above. As in the previous participant, the flat PTC may be indicative of abnormal

cochlear function due to substantial cochlear damage.

The positive results of the TEN test at 3000 and 4000 Hz suggest that cochlear function within this frequency range is grossly impaired in both ears. Results for both the TEN test and the Fast PTCs were essentially symmetrical between ears, suggesting similar cochlear function between ears. However, a substantial difference in speech perception performance was seen between ears. Pure tone thresholds and the audibility provided by the hearing aid were similar between ears. This suggests that radiation on the right side was a potential factor in the difference in speech perception performance between ears. It should be noted that the right ear was tested first, potentially inflating the left ear speech perception results due to learning effects.

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5.3.4: Hearing-Impaired Child Participant #1

Child participant #1 was a 12-year-old male with a history of medulloblastoma who received cisplatin and carboplatin chemotherapies. Hearing thresholds were normal through 2000 Hz sloping to a severe to profound hearing loss at 8000 Hz.

Hearing thresholds were symmetrical between ears. For speech perception testing, the right ear of the participant was selected. Full audibility of the speech stimuli was provided by the hearing aid through 2000 Hz and partial audibility was provided through

4000 Hz.

Speech perception testing in the right ear was more than one standard deviation outside of normal range in the highest filter cut-off conditions across all SNR conditions.

Speech perception performance was like that of the other children with hearing impairment through the 4000 Hz filter cut-off condition. However, in filter cut-off conditions above 4000 Hz, child participant #1 did not have improvements in speech perception and in fact performed slightly poorer with increasing filter cut-off frequency.

Although high-frequency audibility differed between children, speech perception performance in the 6000 and 8000 Hz conditions was poorer in this participant as compared to two children who had less audibility and therefore, less access, to high- frequency speech stimuli. Stated a different way, although child participant #1 had greater access to high-frequency speech stimuli via amplification, he was unable to use

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the speech stimuli for improved speech perception as compared to other participants.

Thus, speech perception performance in the high-frequency filter cut-off conditions suggests this participant did not benefit from high-frequency audibility and has a degradation in performance as additional high-frequency amplification is provided.

Child participant #1 was the only child with abnormal TEN test results. Masked thresholds were 12 dB above TEN presentation level at 4000 HZ in the right ear only.

TEN results between 500 and 2000 Hz in the right ear and 500 Hz and 4000 Hz in the left ear were not elevated. Fast PTCs were obtained at 2000 and 3000 Hz in the right ear but could not be evaluated above 3000 Hz due to the degree of hearing loss. Fast PTC results reveal normal PTCs at 2000 Hz but an abnormal result at 3000 Hz. At 3000 Hz, the PTC slopes down to a frequency near the 3000 Hz probe tone (a typical pattern) but remains flat above the probe. This suggests that the masker continues to be effective at lower levels even as the center frequency rises, a result that seems counterintuitive, because with a sloping high-frequency hearing loss the masker should require notably

HIGHER intensity to continue to mask the lower frequency probe tone. Moore et al.

(1997) noted that a flat tuning curve might be indicative of a complete loss of frequency selectivity. This participant was able to complete a lower-frequency tuning curve and was able to complete the low-frequency section of the PTC, suggesting a clear change in the cochlear function above the 3000 Hz probe tone.

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Results for the right ear of this participant present a clean pattern of abnormal

cochlear function and inability to utilize high-frequency audibility for improved speech perception. The results are in agreement with research suggesting that individuals with substantial cochlear damage perform more poorly with extended high-frequency audibility, particularly in noise (Baer et al., 2002; Vickers et al., 2001). Of note, the high- frequency speech stimuli access provided at the highest filter cut-off frequencies was only the most intense components of the high-frequency speech spectrum. Provision of only these intense high-frequency speech stimuli components may have distorted the

speech signal in the poorest SNR and highest frequency conditions. Of clinical note, this participant and his parent reported minimal hearing aid use because of generally poor sound quality when wearing the hearing aids.

5.4: Study Limitations, Future Research and Clinical Feasibility

The materials and testing procedures used in the current study were selected to

be appropriate for use with adults and children with hearing loss due to chemotherapy

and for use in the audiology clinic. The results of the present study highlight strengths and weaknesses of the test materials, as well as point to limitations of the current research.

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Performance on the MLST for adults with normal hearing reached ceiling

(~100%) at multiple SNR and filter cut-off conditions. Therefore, future use with adults

with normal hearing should use low-pass filter cut-off frequencies and SNR conditions to

elicit performance in the middle of the psychometric function (e.g., below 100%).

Conversely, both groups (especially children) were near 0% performance with the filter

cut-off frequency at 1000 Hz. Future research involving this population may benefit

from use of different speech stimuli for adults and children. Second, elimination of the

1000 Hz condition and addition of a 3000 Hz condition may be beneficial to explore

speech perception across higher filter cut-off frequencies. Finally, inclusion of more

favorable SNR conditions, such as +6 dB or +9 dB, would be expected to provide

additional speech perception information in participant with hearing impairment.

The ability to complete the TEN test is a clear benefit to using the TEN test in the

clinic, as it is a relatively easy task even in young children and is based on fundamental

clinical procedures, making it more likely to be accepted for use in the audiology clinic.

Comparison of Fast PTC task completion rates from the present study with

published completion rates, suggests that the participant with hearing impairment in

this study had unusual difficulty with the Fast PTC task as compared to other groups of participants with high-frequency hearing loss. This is particularly true for completion of

Fast PTCs in the high frequencies (Malicka et al., 2009, 2010; Sęk & Moore, 2011).

Modification to the testing procedures should be implemented to improve completion

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rates. One possible factor affecting the ability to complete the concern with the Fast

PTC task not addressed within this study was the impact of participant focus and

cognitive delay on the ability to complete a successful trial. These concerns are particularly important in participant with chemotherapy as both are secondary effects of chemotherapy (Castellon et al., 2004). Extending the testing time would slow the rate of masker change, which may help overcome these issues. A major concern encountered in PTC evaluation was the lack of reversals seen above the probe frequency. To concentrate testing within the frequency range of interest, the current study protocol evaluated only ½ octave above the probe frequency. Increasing the frequency range of a trial to a full octave above the probe frequency will increase the total number of reversals, facilitating tip frequency determination with the Quadratic

Function estimation method. The results of the current study suggest that further investigation and modification of the Fast PTC task is warranted in participant with hearing loss due to chemotherapy before use in a clinical setting.

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Chapter 6: Final Conclusions

The results of this feasibility study highlight the critical need for evaluation of

speech perception in individuals with hearing loss due to chemotherapy. Hearing-

impaired participants generally had poorer speech perception across all filter cut-off

frequencies and SNR conditions when compared to normal-hearing controls. Speech perception performance for adults with hearing impairment tended to be farther from the normal hearing average as compared to children with hearing impairment because performance by children with normal hearing was poorer that the adults with normal hearing. In addition, participants with hearing impairment had smaller gains in speech perception with additional high-frequency audibility as compared to normal-hearing controls.

In this study, measures of cochlear function were utilized to identify regions of substantial cochlear damage. In addition to providing normal results for all participant when hearing thresholds were normal to near normal, results of the TEN test revealed two participant with hearing impairment that met the criteria for abnormal cochlear function in the high frequencies. These participants also had smaller improvements in speech perception as compared to other participant with hearing impairment. Thus, the

TEN test was able to identify participant who not only had comparatively poorer speech perception overall, but also little improvement as additional audibility was provided.

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Fast PTCs were successful in identification of normal cochlear function in regions of

normal hearing for adults with hearing impairment. However, participant with hearing impairment were unable to complete the task when high frequencies were evaluated, regardless of the degree of hearing loss. In addition, the children with hearing impairment had tremendous difficulty with the task across frequencies. The inability to complete high frequency PTCs limited the utility of the Fast PTC test for identifying participants with substantial cochlear damage. This also prevented making any meaningful comparisons between the TEN test and Fast PTCS.

Results from this study highlight future research needs. Comparison of speech perception abilities between participant with hearing loss due to chemotherapy and participant with hearing loss due to other etiologies may help to illustrate the unique speech perception difficulties due to chemotherapy. Further research should also investigate the impact of additional interventions, specifically radiation, as radiation likely affected the speech perception of some participant. Use of a cognitive assessment for participants who have received radiation and chemotherapy is strongly indicated in order to determine the impact of cognitive delays on speech perception tasks. Based on this study, a focus on additional filter cut-off frequencies (such as starting at 2000 Hz and including 3000 Hz) and additional SNR conditions (starting at 0 dB SNR and including +6 dB or +9 dB SNR) may be more appropriate when investigating speech perception in future studies of participant with hearing impairment.

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Further evaluation of both speech perception abilities and cochlear function, particularly using the TEN test, may help strengthen correlations between the two measures, helping to identify individuals with abnormal cochlear function and speech perception difficulties including the inability to utilize high-frequency audibility. The information provided by the tests can help to illustrate the speech perception issues of individuals with hearing loss due to chemotherapy and may provide insight into potential clinical interventions going forward.

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Appendix A: Curve-fitting procedures for the Fast-PTC software

The Fast PTC Software provides five different curve fitting procedures that are used to determine the tip frequency of a tuning curve. Appendix A provides a description of each of the curve fitting procedures. In addition, a screen shot of the results for each procedure on a tuning curve with a 2000 Hz probe tone. The screen shot shows the curve fit to the tuning curve as well as the tip frequency estimated by the procedure.

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Double Linear Regression (DLR): Slopes of high and low frequency sides are determined. the minimum is the crossing points of the best fitting straight lines.

Figure 15 is a screen shot of the DLR analysis for the raw PTC shown in Figure 3.

Figure 15: Double Linear Regression analysis for a 2000 Hz PTC.

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Moving Average: An average between two (two-point moving average or TPMA) or four (four-point moving average or FPMA) consecutive reversals is made and the minimum is taken as the tip frequency. Figure 16 is a screen shot of the Two and

Four Point Moving Average analysis for the raw PTC shown in Figure 3.

Figure 16: Two and Four Point Moving Average analysis for a 2000 Hz PTC.

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Quadratic Function: First, a TPMA is fit to the data with the lowest point assigned at

Flow. A quadratic function (QF) is then fit to the frequencies between 0.65 and 1.35

Flow and the tip frequency is the lowest point on this curve. Figure 17 is a screen

shot of the Quadratic Function analysis for the raw PTC shown in Figure 3.

Figure 17: Quadratic Function analysis for a 2000 Hz PTC.

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Double Low-Pass Filtering (DLF): Raw data are low-pass filtered via a 3rd order

Butterworth digital filter resulting in a linear phase shift. To remove this phase shift, data are reversed and filtered a second time. Three different low-pass filters are used. The low-pass filters are expressed in terms of the Nyquist Frequency (NqFrq) and include 0.25 X NqFrq, 0.2 X NqFrq and 0.15 X NqFrq. The lowest point on the curve after filtering is the tip frequency. This results in three different tip estimates

(DLF.25, DLF.20 and DLF.15). See Sęk et al. (2007) and Myers and Malicka (2014) for additional explaination. Figure 18 is a screen shot of the three DLF analyses for the

PTC in Figure 3.

Figure 18: Three variations of the Double Low-Pass Filtering analysis for a 2000 Hz PTC.

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Rounded-exponential function (RoEx): The RoEx was developed as a model of the cochlear auditory frequency shape (Patterson et al, 1982). Here, the lowest point on the data is determined and a RoEx is fit to both the low frequency side of the curve

(0.75 Flow to 1 Flow) and the high frequency side (1 Fhigh to 1.25 Fhigh). The intersection of the two is taken as the tip frequency. Figure 19 is the RoEx analysis for the 2000

Hz PTC in Figure 3.

Figure 19: RoEx analysis for a 2000 Hz PTC.

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Appendix B: Examples of Audibility Verification

An example of the Verifit Speechmapping screen is presented below in Figure 20.

Here, the hearing aid was programmed with thresholds at 15 dB HL from 250 to 8000 Hz

representing the settings used for all normal-hearing control participant in this study. A left ear threshold is presented in blue while a right ear threshold is presented in red.

The yellow gold “+” symbols represent the MPO target for a 90 dB SLP input and are typically close to the output limits of the hearing aid. The gold line is the actual output of the hearing aid in response to a 90 dB SPL pure tone sweep. Note that here, the MPO target does not exceed 95 dB SPL and the output does not exceed 93 dB SPL. The Green

“+” symbol represents the DSL 5.0 child target for a female speaker at 65 dB SPL and green line represents the output of the hearing aid to a calibrated female speaker at 65 dB SPL. The magenta shaded area is the LTSS and the solid magenta line is the average of the LTSS for the speech stimuli used in this study. The hearing aid was programmed for each participant so that the magenta line is as close a match to the green “+” as possible. With a few exceptions, the average LTSS of the study speech stimuli are close the level of the calibrated female speech stimuli.

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Figure 21 is the verification screen for hearing-impaired child participant #5. All

symbols are the same as on Figure 17, with the addition of audibility lines. The vertical teal line shows the full audibility cut-off frequency (here, 4000 Hz) and the vertical blue line shows the partial audibility cut-off frequency (here, 6000 Hz). Full audibility was defined to be the highest frequency at which the lower edge of the spectrum was 5 dB above the participant’s threshold. Partial audibility was determined to be the highest frequency at which the midpoint of the speech spectrum was 5 dB above the participant’s threshold.

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Figure 20: Screenshot of graphic and tabular results of Verifit 2 Speechmapping for normal-hearing control participants.

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Figure 21: Screenshot of graphic and tabular results of Verifit 2 Speechmapping for hearing-impaired child participant #5 with audibility cut-off frequencies noted.

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Appendix C: Adult and child average TEN thresholds with standard deviation for each

frequency and intensity level

Adult Child

30 dB HL 50 dB HL 70 dB HL 30 dB HL 50 dB HL 70 dB HL

500 Hz 500 Hz

Average 29.35 48.26 68.19 30.17 49.59 70.31 SD 1.85 1.69 1.89 2.45 2.38 2.55 1000 Hz 1000 Hz

Average 29.23 49.35 69.16 30.34 50.07 70.31 SD 1.54 2.12 1.94 1.92 1.95 2.17 2000 Hz 2000 Hz

Average 29.35 48.65 69.23 30.47 50.37 70.78 SD 1.99 1.98 2.441 1.85 2.22 2.18 4000 Hz 4000 Hz

Average 27.68 48.13 69.94 29.22 49.53 70.95

SD 1.522 1.78 2.6 2.02 1.82 2.53

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Appendix D: Fast PTC Rejection Criteria

The developer of the Fast PTC software recommends that specific criteria should be met for the program to best calculate tip frequency, (Myers & Malicka, 2014). The first criterion for acceptance is that a PTC must have a sharply delineated tip. PTCs are rejected if the tip frequency region is flat with a width wider than 0.2 Fs (Figure 22).

Figure 22: Screenshot of raw data for a 2000 Hz PTC with abnormally flat region near tip frequency.

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The second criterion for acceptance is that a PTC must have only a single tip. The

PTC is rejected if “w” shaped (Figure 23). The addition of a low-frequency masking noise is used to reduce the potential for “w” shaped PTCs.

Figure 23: Screenshot of raw data for a 2000 Hz PTC with abnormal “w” shape.

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The final criterion for acceptance is that there should be only small level differences between reversals. The authors suggest that the PTC should be rejected if level differences of more than 30 dB are present (Figure 24). Note that this criterion was modified for the current study and is described further in the discussion section.

Figure 24: Screenshot of raw data for a 4000 Hz PTC with abnormally long level difference (here greater than 50 dB).

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Appendix E: Audibility and Speech Perception for Hearing-Impaired Participants

Appendix E includes the Verifit Speechmapping information and speech perception performance for each participant with hearing impairment. On the

Speechmapping screenshot, the blue line is the threshold in dB SPL. The yellow “+” symbols are the MPO target with the corresponding yellow line the output of the hearing aid in response to a 90 dB SPL swept pure tone. The green “+” symbols are the target average LTSS output for a calibrated female speech stimulus presented at 65 dB

SPL. The green line is the average LTSS response of the hearing aid. The shaded purple area is the LTSS for the study speech stimulus and the solid purple line is the average

LTSS. Note that the hearing aid was programmed so that the purple line was as close a match to the GREEN “+” as possible. Tabular results are provided below the graphs.

Hearing-impaired adult participant speech perception data are compared to the average (±2 standard deviation) normal-hearing participant data. For all figures, normal-hearing results are presented in greyscale. The green circles and line indicate the percent correct score across filter cut-off frequency in the +3 dB SNR condition, the blue triangle and line indicate the 0 dB SNR condition and the red square and line denote the –3 SNR condition.

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